Spiropyrrolidine beta-secretase inhibitors for the treatment of alzheimer&#39;s disease

ABSTRACT

The present invention is directed to spiropyrrolidine compounds of formula (I) which are inhibitors of the beta-secretase enzyme and that are useful in the treatment of diseases in which the beta-secretase enzyme is involved, such as Alzheimer&#39;s disease. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the treatment of such diseases in which the beta-secretase enzyme is involved.

FIELD OF THE INVENTION

The invention is directed to spiropyrrolidine compounds which are usefulas inhibitors of the beta secretase enzyme, and are useful in thetreatment of diseases in which the beta secretase enzyme is involved,such as Alzheimer's Disease.

BACKGROUND OF THE INVENTION

Alzheimer's disease is characterized by the deposition of amyloid in thebrain in the form of extra-cellular plaques and intra-cellularneurofibrillary tangles. The rate of amyloid accumulation is a functionof the rates of formation, aggregation and egress from the brain. It isgenerally accepted that the main constituent of amyloid plaques is the 4kD amyloid protein (βA4, also referred to as Aβ, β-protein and βAP)which is a proteolytic product of a precursor protein of much largersize. The amyloid precursor protein (APP or AβPP) has a receptor-likestructure with a large ectodomain, a membrane spanning region and ashort cytoplasmic tail. The Aβ domain encompasses parts of bothextra-cellular and transmembrane domains of APP, thus its releaseimplies the existence of two distinct proteolytic events to generate itsNH₂- and COOH-termini. At least two secretory mechanisms exist whichrelease APP from the membrane and generate soluble, COOH-truncated formsof APP (APP_(S)). Proteases that release APP and its fragments from themembrane are termed “secretases.” Most APP_(S) is released by a putativeα-secretase which cleaves within the Aβ protein to release α-APP_(S) andprecludes the release of intact Aβ. A minor portion of APP_(S) isreleased by a β-secretase (“β-secretase”), which cleaves near theNH₂-terminus of APP and produces COOH-terminal fragments (CTFs) whichcontain the whole Aβ domain.

Thus, the activity of β-secretase or β-site amyloid precursorprotein-cleaving enzyme (“BACE”) leads to the cleavage of APP,production of Aβ, and accumulation of β-amyloid plaques in the brain,which is characteristic of Alzheimer's disease (see R. N. Rosenberg,Arch. Neurol., vol. 59, September 2002, pp. 1367-1368; H. Fukumoto etal, Arch. Neurol., vol. 59, September 2002, pp. 1381-1389; J. T. Huse etal, J. Biol. Chem., vol 277, No. 18, issue of May 3, 2002, pp.16278-16284; K. C. Chen and W. J. Howe, Biochem. Biophys. Res. Comm,vol. 292, pp 702-708, 2002). Therefore, therapeutic agents that caninhibit β-secretase or BACE may be useful for the treatment ofAlzheimer's disease.

The compounds of the present invention are useful for treatingAlzheimer's disease by inhibiting the activity of β-secretase or BACE,thus preventing the formation of insoluble Aβ and arresting theproduction of Aβ.

SUMMARY OF THE INVENTION

The present invention is directed to spiropyrrolidine compounds ofgeneral formula (I)

and pharmaceutically acceptable salts thereof, which are useful asinhibitors of the β-secretase enzyme.

The invention is also directed to pharmaceutical compositions whichinclude a therapeutically effective amount of a compound of formula (I),or pharmaceutically acceptable salts thereof, and a pharmaceuticallyacceptable carrier. The invention is also directed to methods oftreating mammals for diseases in which the β-secretase enzyme isinvolved, such as Alzheimer's disease, and the use of the compounds andpharmaceutical compositions of the invention in the treatment of suchdiseases.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention is directed to spiropyrrolidinecompounds represented by general formula (I)

and pharmaceutically acceptable salts thereof, wherein:V is selected from the group consisting of

(1) C, or

(2) N, and the dotted line leading to V represents an optional doublebond, and is present

when V is C and is absent when V is N;

or V is selected from the group consisting of

(1) C, or

(2) N, and the real line and optional dotted line leading to V representa single bond or an optional double bond, and represent a single bondwhen V is N;

Q is selected from the group consisting of

(1) ═CR¹⁰—,

(2)═N—,

(3) —(N→O)—,

(4) —O—, or

(5)═S—;

Y is selected from the group consisting of

(1) ═CR¹⁰—,

(2) —CR¹⁰═,

(3) ═CR¹⁰—CR¹¹═,

(4) ═CR¹⁰—N═, or

(5) ═N—CR¹⁰═;

Z is selected from the group consisting of

(1) ═CR¹⁰—,

(2) —N—,

(3) —O—, or

(4) ═S—;

provided that Q, Y and Z together with V and the neighboring C atom forma fused aromatic 5- or 6-membered ring;X¹-X² is selected from the group consisting of

(1) —CR¹⁰R¹¹—CR¹²CR¹³,

(2) —CR¹⁰R¹¹—O—,

(3) —O—CR¹⁰R¹¹—,

(4) —CR¹⁰R¹¹—NR¹²—,

(5) —NR¹²—CR¹⁰R¹¹—,

(6) —CR¹⁰R¹¹—S(═O)mR¹²—,

(7) —S(═O)mR¹²—, CR¹⁰R¹¹—,

(8) —CR¹⁰R¹¹—CR¹²CR¹³—O—,

(9) —CR¹⁰R¹¹—CR¹²CR¹³—,

(10) —CR¹⁰R¹¹—O—CR¹²CR¹³,

(11) —CR¹⁰R¹¹—CR¹²CR¹³NR¹⁴—, or

(12) —O—CR¹⁰R¹¹—CR¹²CR¹³—, or

(13) —S(═O)pR¹²—CR¹⁰R¹¹—;

R¹ is selected from the group consisting of

-   -   (1) hydrogen    -   (2) C₁₋₆alkyl,    -   (3) C₂₋₆alkenyl,    -   (4) —C₃₋₉ cycloalkyl,    -   (5) —C₆₋₁₀aryl,    -   (6) heteroaryl group having from 5 to 12 ring atoms, wherein at        least one ring atom is a heteroatom selected from the group        consisting of nitrogen, sulfur or oxygen,    -   (7) a heterocyclic group having 4 to 8 ring atoms, wherein at        least one ring atom is a heteroatom selected from the group        consisting of nitrogen, sulfur or oxygen,    -   wherein said alkyl, alkenyl, aryl, cycloalkyl, heterocyclic or        heteroaryl R¹ moiety is optionally substituted with one or more        -   (a) halo,        -   (b) —OH,        -   (c) —CN,        -   (d) —C₁₋₆ alkyl,        -   (e) —C₃₋₈ cycloalkyl,        -   (f) —O—C₁₋₆ alkyl,        -   (g) —O—CH₂—C₆₋₁₀aryl,        -   (h) —C₆₋₁₀aryl,        -   (i) heteroaryl group having from 5 to 12 ring atoms, wherein            at least one ring atom is a heteroatom selected from the            group consisting of nitrogen, sulfur or oxygen,        -   (j) oxo,        -   (k) a heterocyclic group having 4 to 8 ring atoms, wherein            at least one ring atom is a heteroatom selected from the            group consisting of nitrogen, sulfur or oxygen,        -   (l) —O—CH₂—C₃₋₈ cycloalkyl,        -   (m) —C(═O)—C₁₋₆ alkyl, or        -   (n) —NR^(5A)R^(5B),            R² and R³ are independently selected from the group            consisting of:    -   (1) hydrogen,    -   (2) OH,    -   (3) —C₁₋₆ alkyl,    -   (4) —CN,    -   (5) —C₆₋₁₀ aryl, or    -   (6) heteroaryl group having from 5 to 12 ring atoms, wherein at        least one ring atom is a heteroatom selected from the group        consisting of nitrogen, sulfur or oxygen,    -   wherein said alkyl, aryl or heteroaryl R² or R³ moiety is        optionally substituted with one or more        -   (a) halo,        -   (b) —C₁₋₆ alkyl, wherein said alkyl is optionally            substituted with one or more halogen, and        -   (c) —O—C₁₋₆ alkyl,            or R² and R³ are linked together to form cyclic group of            4-10 ring carbon atoms, wherein one or two of the ring            carbon atoms is replaced by an oxygen, nitrogen or sulfur;            R^(5A) and R^(5B) are independently selected from the group            consisting of    -   (1) hydrogen,    -   (2) —C₁₋₆ alkyl,    -   (3) —C(═O)—(O)_(m)—C₁₋₆ alkyl,    -   (4) —C(═O)—(O)_(m)—C₆₋₁₀ aryl,    -   (5) —SO₂—C₃₋₈ cycloalkyl,    -   (6) —SO₂—C₁₋₆ alkyl,    -   (4) —C(═O)—NR^(6A)R^(6B), wherein R^(6A) and R^(6B) are selected        from the group consisting of wherein the alkyl, cycloalkyl or        aryl moiety is optionally substituted with one or more        -   (a) halogen,        -   (b) hydroxyl,        -   (c) —O—C₁₋₆ alkyl, or        -   (d) —C(═O)—(O)_(m)—C₁₋₆ alkyl,    -   or R^(6A) and R^(6B) are linked together with the nitrogen to        which they are attached to form a 4-6 membered carbocyclic ring,        wherein one or two of the ring carbon atoms is optionally        replaced by a nitrogen, oxygen or sulfur, and the ring is        optionally substituted with one or more        -   (a) halogen,        -   (b) hydroxyl,        -   (c) C₁₋₆ alkyl,        -   (d) —O—C₁₋₆ alkyl,        -   (e) —C(═O)—(O)_(m)—C₁₋₆ alkyl, or        -   (f) —SO₂—C₁₋₆ alkyl;            R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ are independently selected from            the group consisting of:    -   (1) hydrogen,    -   (2) —C₁₋₆ alkyl,    -   (3) hydroxyl,    -   (4) —(CH₂)_(m) C₆₋₁₀aryl    -   (5) —C₂₋₆alkenyl,    -   (6) —O—C₁₋₆alkyl,    -   (7) halogen,    -   (8) —SO₂—C₁₋₆alkyl,    -   (9)-NR^(5A)R^(5B),    -   (10) —C₃₋₈ cycloalkyl,    -   (11) —C(═O)—(O)_(m)—C₁₋₆ alkyl,    -   (12) —C(═O)—(O)_(m)—C₆₋₁₀ aryl,    -   (13) —C(═O)—NH—C₁₋₆ alkyl,    -   (14) —S(═O)₂—C₆₋₁₀ aryl,    -   wherein said alkyl, cycloalkyl, alkenyl or aryl moiety is        optionally substituted with one or more        -   (a) halo,        -   (b) hydroxyl,        -   (c) —C₁₋₆ alkyl,

(d) —NR^(5A)R^(5B),

-   -   (e) —O—C₁₋₆ alkyl, and    -   (f) —C₆₋₁₀aryl,    -   wherein said wherein said alky or aryl is optionally substituted        with one or more halo,    -   or any R¹⁰ and R¹¹, or any R¹² and R¹³, on identical carbon ring        atoms, are linked together to form an oxo group,    -   or any R¹⁰ and R¹¹, or any R¹² and R¹³, on identical carbon ring        atoms, are linked together to form an aromatic or non-aromatic        spirocyclic group of 5-10 ring carbon atoms, wherein one or two        of the ring carbon atoms is replaced by an oxygen, nitrogen or        sulfur,    -   or any R¹⁰ and R¹¹, or any R¹² and R¹³, on adjacent carbon ring        atoms, are linked together to form to form a fused aromatic or        non-aromatic cyclic group of 5-10 ring carbon atoms, wherein one        or two of the ring carbon atoms is replaced by an oxygen,        nitrogen or sulfur,        m is 0 or 1;        n is 0 or 1;        p is 0, 1 or 2;        and pharmaceutically acceptable salts thereof.

In particular embodiments of the compounds of formula (I), V is C andthe dotted line leading to V represents a double bond. In otherembodiments of the compounds of formula (I), V is n and the dotted lineleading to V is absent.

In particular embodiments of the compounds of formula (I), -Q-Y—Z—together form the group —CR¹⁰═CR¹⁰—CR¹¹═CR¹⁰—, thereby forming a fusedphenyl ring.

In other embodiments of the compounds of formula (I), -Q-Y—Z— togetherforms the groups —N═CR¹⁰—CR¹¹═CR¹⁰— or —CR¹⁰═CR¹⁰—CR¹¹═N—, therebyforming a fused pyridyl ring.

In other embodiments of the compounds of formula (I), -Q-Y—Z— togetherforms the group —N═CR¹⁰—CR¹¹═N— or —N═CR¹⁰—N═CR¹¹—, thereby forming afused pyrimidinyl ring.

In other embodiments of the compounds of formula (I), -Q-Y—Z— togetherforms the group —NH—CR¹⁰═CR¹⁰—, —S—CR¹⁰═CR¹⁰—, —O—CR¹⁰═CR¹⁰—,—N═CR¹⁰—S—, —CR¹⁰═CR¹⁰═S— or —CR¹⁰═CR¹⁰—O—, thereby forming afive-membered heteroaryl ring.

In particular embodiments of the compounds of formula (I), X¹-X² is—CR¹⁰R¹¹—CR¹²CR¹³— and n is 0 or 1.

In other embodiments X¹-X² is —NR¹²—CR¹⁰R¹¹— or CR¹⁰R¹¹—NR¹²— and n is1.

In other embodiments, X¹-X² is —S(═O)pR¹²—CR¹⁰R¹¹— and n is 1.

In other embodiments, X¹-X² is —CR¹⁰R¹¹—O— or —O—CR¹⁰R¹¹—, and n is 1.

In other embodiments, X¹-X² is one of —CR¹⁰R¹¹—NR¹⁴CR¹²R¹³—,—CR¹⁰R¹¹—O—CR¹²CR¹³—, —CR¹⁰R¹¹—CR¹⁴CR¹²NR¹³—, or —O—CR¹⁰R¹¹—CR¹²CR¹³—.

In particular embodiments of the compounds of formula (I), R¹ isselected from the group consisting of

-   -   (1) hydrogen    -   (2) C₁₋₆alkyl,    -   (3) C₃₋₉ cycloalkyl, or    -   (4) phenyl,    -   wherein said alkyl, cycloalkyl or phenyl R¹ moiety is optionally        substituted with one or more        -   (a) halo,        -   (b) —OH,        -   (c) —CN,        -   (d) —C₁₋₆ alkyl        -   (e) —C₃₋₆ cycloalkyl, or        -   (f) —O—C₁₋₆ alkyl.

In particular embodiments, R¹ is hydrogen, phenyl (optionallysubstituted with halogen), or cyclohexyl.

In particular embodiments of the compounds of formula (I), R² ishydrogen and R³ is selected from the group consisting of:

-   -   (1) hydrogen,    -   (2) C₆₋₁₀aryl (for example, phenyl), or    -   (3) heteroaryl,    -   wherein said aryl or heteroaryl R³ moiety is optionally        substituted with one or more        -   (a) halo,        -   (b) —C₁₋₆ alkyl, wherein said alkyl is optionally            substituted with one or more halogen, and        -   (c) —O—C₁₋₆ alkyl.

In particular embodiments, R² is hydrogen and R³ is hydrogen orunsubstituted phenyl.

In other embodiments, R² and R³ are linked together to form cyclic groupof 4-10 ring carbon atoms, wherein one or two of the ring carbon atomsis replaced by an oxygen, nitrogen or sulfur.

The invention is also directed to methods of treating mammals fordiseases in which the β-secretase enzyme is involved, such asAlzheimer's disease, by administering a therapeutically effective amountof a compound of any of the embodiments of formula (I).

The invention is also directed to pharmaceutical compositions whichinclude an effective amount of a compound of any of the embodiments offormula (I) or pharmaceutically acceptable salts thereof, and apharmaceutically acceptable carrier.

The invention is further directed to a method for the manufacture of amedicament or a composition for inhibiting β-secretase enzyme activityin humans and animals comprising combining a compound of any of theembodiments of formula (I) or a pharmaceutically acceptable saltthereof, with a pharmaceutical carrier or diluent.

In one embodiment, the invention is directed to methods of inhibitingBACE1 enzyme activity, by administering a therapeutically effectiveamount of a compound of any of the embodiments of formula (I).

In another embodiment, the invention is directed to methods ofinhibiting BACE2 enzyme activity, by administering a therapeuticallyeffective amount of a compound of any of the embodiments of formula (I).

The invention is also directed to a method for the manufacture of amedicament or a composition for treating Alzheimer's Disease in humans,comprising combining a compound of any of the embodiments of formula (I)or a pharmaceutically acceptable salt thereof, with a pharmaceuticalcarrier or diluent.

In some embodiments, the compound of formula (I) is a compound offormula (II)

and pharmaceutically acceptable salts thereof, wherein R², R⁵, X¹, X²,Q, Y and Z are as defined above.

In particular embodiments of the compounds of formula (II), -Q-Y—Z—together form the group —CR¹⁰═CR¹⁰—CR¹¹═CR¹⁰—, thereby forming a fusedphenyl ring.

In other embodiments of the compounds of formula (II), -Q-Y—Z— togetherforms the groups —N═CR¹⁰—CR¹¹═CR¹⁰— or —CR¹⁰═CR¹⁰—CR¹¹═N—, therebyforming a fused pyridyl ring.

In other embodiments of the compounds of formula (II), -Q-Y—Z— togetherforms a the group —N═CR¹⁰—CR¹¹═N— or —N═CR¹⁰—N═CR¹¹, thereby forming afused pyrimidinyl ring.

In other embodiments of the compounds of formula (II), -Q-Y—Z— togetherforms the group —NH—CR¹⁰═CR¹⁰—, —S—CR¹⁰═CR¹⁰—, —O—CR¹⁰═CR¹⁰—,—N═CR¹⁰—S—, —CR¹⁰═CR¹⁰═S— or —CR¹⁰═CR¹⁰—O—, thereby forming afive-membered heteroaryl ring.

In particular embodiments of the compounds of formula (II), X¹-X² is—CR¹⁰R¹¹—CR¹²CR¹³— and n is 0 or 1.

In other embodiments of the compounds of formula (II), X¹-X² is—NR¹²—CR¹⁰R¹¹— or CR¹⁰R¹¹— and n is 1.

In other embodiments of the compounds of formula (II), X¹-X² is—S(═O)pR¹²—CR¹⁰R¹¹— and n is 1.

In other embodiments of the compounds of formula (II), X¹-X² is—CR¹⁰R¹¹—O— or —O—CR¹⁰R¹¹—, and n is 0 or 1.

In other embodiments of the compounds of formula (II), X¹-X² is one of—CR¹⁰R¹¹—NR¹⁴CR¹²R¹³—, —CR¹⁰R¹¹—O—CR¹²CR¹³—, —CR¹⁰R¹¹—CR¹⁴CR¹²NR¹³—, or—O—CR¹⁰R¹¹—CR¹²CR¹³—.

In particular embodiments of the compounds of formula (II), R² ishydrogen and R³ is selected from the group consisting of:

-   -   (1) hydrogen,    -   (2) aryl (for example, phenyl), or    -   (3) heteroaryl,    -   wherein said aryl or heteroaryl R³ moiety is optionally        substituted with one or more        -   (a) halo,        -   (b) —C₁₋₆ alkyl, wherein said alkyl is optionally            substituted with one or more halogen, and        -   (c) —O—C₁₋₆ alkyl.

In particular embodiments of the compounds of formula (II), R² ishydrogen and R³ is hydrogen or unsubstituted phenyl.

In some embodiments, the compound of formula (I) is a compound offormula (III)

and pharmaceutically acceptable salts thereof, wherein R², R⁵, X¹, X²,Q, Y and Z are as defined above.

In particular embodiments of the compounds of formula (III), -Q-Y—Z—together form the group —CR¹⁰═CR¹⁰—CR¹¹═CR¹⁰—, thereby forming a fusedphenyl ring.

In other embodiments of the compounds of formula (III), -Q-Y—Z— togetherforms the groups —N═CR¹⁰—CR¹¹═CR¹⁰— or —CR¹⁰═CR¹¹═N—, thereby forming afused pyridyl ring.

In other embodiments of the compounds of formula (III), -Q-Y—Z— togetherforms the group —N═CR¹⁰—CR¹¹═N— or —N═CR¹⁰—N═CR¹¹—, thereby forming afused pyrimidinyl ring.

In other embodiments of the compounds of formula (III), -Q-Y—Z— togetherforms the group —NH—CR¹⁰═CR¹⁰—, —S—CR¹⁰═CR¹⁰—, —O—CR¹⁰═CR¹⁰—,—N═CR¹⁰—S—, —CR¹⁰═CR¹⁰═S— or —CR¹⁰═CR¹⁰—O—, thereby forming afive-membered heteroaryl ring.

In particular embodiments of the compounds of formula (III), X¹-X² is—CR¹⁰R¹¹—CR¹²CR¹³— and n is 0 or 1

In other embodiments of the compounds of formula (III), X¹-X² isNR¹²—CR¹⁰R¹¹— or —CR¹⁰R¹¹—NR¹²— and n is 1.

In other embodiments of the compounds of formula (III), X¹-X² is—S(═O)pR¹²—CR¹⁰R¹¹— and n is 1.

In other embodiments of the compounds of formula (III), X¹-X² is—CR¹⁰R¹¹—O— or —O—CR¹⁰R¹¹—, and n is 1.

In other embodiments of the compounds of formula (III), X¹-X² is one of—CR¹⁰R¹¹—NR¹⁴CR¹²R¹³—, —CR¹⁰R¹¹—O—CR¹²CR¹³—, —CR¹⁰R¹¹—CR¹⁴CR¹²NR¹³—, or—O—CR¹⁰R¹¹—CR¹²CR¹³—.

In some embodiments, the compound of formula (I) is a compound offormula (IV)

and pharmaceutically acceptable salts thereof, wherein R², R³, R⁴, R⁵,X¹ and X² are as defined above.

In particular embodiments of the compounds of formula (IV), X¹-X² is—CR¹⁰R¹¹—CR¹²CR¹³— and n is 0 or 1.

In other embodiments of the compounds of formula (IV), X¹-X² isNR¹²—cR¹⁰R¹¹— or —CR¹⁰R¹¹—NR¹²— and n is 1.

In other embodiments of the compounds of formula (IV), X¹-X² is—S(═O)pR¹²—CR¹⁰R¹¹— and n is 1.

In other embodiments of the compounds of formula (IV), X¹-X² iscR¹⁰R¹¹—O— or —O—CR¹⁰R¹¹— and n is 1 or 2.

In other embodiments of the compounds of formula (IV), X¹-X² is one of—CR¹⁰R¹¹—NR¹⁴CR¹²R¹³—, —CR¹⁰R¹¹—O—CR¹²CR¹³—, —CR¹⁰R¹¹—CR¹⁴CR¹²NR¹³—, or—O—CR¹⁰R¹¹—CR¹²CR¹³—.

In particular embodiments of the compounds of formula (IV), R¹ isselected from the group consisting of

-   -   (1) hydrogen    -   (2) C₁₋₆alkyl,    -   (3) C₃₋₆ cycloalkyl, or    -   (4) phenyl,        -   wherein said alkyl, cycloalkyl or phenyl R¹ moiety is            optionally substituted with one or more        -   (a) halo,        -   (b) —OH,        -   (c) —CN,        -   (d) —C₁₋₆ alkyl        -   (e) —C₃₋₆ cycloalkyl, or        -   (f) —O—C₁₋₆ alkyl.

In particular embodiments of the compounds of formula (IV), R¹ ishydrogen, phenyl (optionally substituted with halogen), or cyclohexyl.

In particular embodiments of the compounds of formula (IV), R² ishydrogen and R³ is selected from the group consisting of:

-   -   (1) hydrogen,    -   (2) aryl (for example, phenyl), or    -   (3) heteroaryl,    -   wherein said aryl or heteroaryl R³ moiety is optionally        substituted with one or more        -   (a) halo,        -   (b) —C₁₋₆ alkyl, wherein said alkyl is optionally            substituted with one or more halogen, and        -   (c) —O—C₁₋₆ alkyl.

In particular embodiments of the compounds of formula (IV), R² ishydrogen and R³ is hydrogen or unsubstituted phenyl.

In other embodiments of the compounds of formula (IV), R² and R³ arelinked together to form cyclic group of 4-10 ring carbon atoms, whereinone or two of the ring carbon atoms is replaced by an oxygen, nitrogenor sulfur.

In some embodiments, the compound of formula (I) is a compound offormula (V)

and pharmaceutically acceptable salts thereof, wherein R², R³, R⁴, R⁵,X¹ and X² are as defined above.

In particular embodiments of the compounds of formula (V), X¹-X² is—CR¹⁰R¹¹—CR¹²CR¹³— and n is 0 or 1

In other embodiments of the compounds of formula (V), X¹-X² isNR¹²—CR¹⁰R¹¹— or —CR¹⁰R¹¹—NR¹²— and n is 1.

In other embodiments of the compounds of formula (V), X¹-X² is—S(═O)pR¹²—CR¹⁰R¹¹— and n is 1.

In other embodiments of the compounds of formula (V), X¹-X² is—CR¹⁰R¹¹—O— or —O—CR¹⁰R¹¹—, and n is 1.

In other embodiments of the compounds of formula (V), X¹-X² is one of—CR¹⁰R¹¹—NR¹⁴CR¹²R¹³—, —CR¹⁰R¹¹—O—CR¹⁴CR¹²NR¹³—, or—O—CR¹⁰R¹¹—CR¹²CR¹³—.

In particular embodiments of the compounds of formula (V), R¹ isselected from the group consisting of

-   -   (1) hydrogen    -   (2) C₁₋₆alkyl,    -   (3) C₃₋₆ cycloalkyl, or    -   (4) phenyl,    -    wherein said alkyl, cycloalkyl or phenyl R¹ moiety is        optionally substituted with one or more        -   (a) halo,        -   (b) —OH,        -   (c) —CN,        -   (d) —C₁₋₆ alkyl        -   (e) —C₃₋₆ cycloalkyl, or        -   (f) —O—C₁₋₆ alkyl.

In particular embodiments of the compounds of formula (V), R¹ ishydrogen, phenyl (optionally substituted with halogen), or cyclohexyl.

In particular embodiments of the compounds of formula (V), R² ishydrogen and R³ is selected from the group consisting of:

-   -   (1) hydrogen,    -   (2) aryl (for example, phenyl), or    -   (3) heteroaryl,    -   wherein said aryl or heteroaryl R³ moiety is optionally        substituted with one or more        -   (a) halo,        -   (b) —C₁₋₆ alkyl, wherein said alkyl is optionally            substituted with one or more halogen, and        -   (c) —O—C₁₋₆ alkyl.

In particular embodiments of the compounds of formula (V), R² ishydrogen and R³ is hydrogen or unsubstituted phenyl.

In other embodiments of the compounds of formula (V), R² and R³ arelinked together to form cyclic group of 4-10 ring carbon atoms, whereinone or two of the ring carbon atoms is replaced by an oxygen, nitrogenor sulfur.

The invention is also directed to methods of treating mammals fordiseases in which the β-secretase enzyme is involved, such asAlzheimer's disease, by administering a therapeutically effective amountof a compound of any of the embodiments of formulas (II) to (V).

The invention is also directed to pharmaceutical compositions whichinclude an effective amount of a compound of any of the embodiments offormulas (II) to (V) or pharmaceutically acceptable salts thereof, and apharmaceutically acceptable carrier.

The invention is further directed to a method for the manufacture of amedicament or a composition for inhibiting β-secretase enzyme activityin humans and animals comprising combining a compound of any of theembodiments of formulas (II) to (V) or a pharmaceutically acceptablesalt thereof, with a pharmaceutical carrier or diluent.

In one embodiment, the invention is directed to methods of inhibitingBACE1 enzyme activity, by administering a therapeutically effectiveamount of a compound of any of the embodiments of formulas (II) to (V).

In another embodiment, the invention is directed to methods ofinhibiting BACE2 enzyme activity, by administering a therapeuticallyeffective amount of a compound of any of the embodiments of formulas(II) to (V).

The invention is also directed to a method for the manufacture of amedicament or a composition for treating Alzheimer's Disease in humans,comprising combining a compound of any of the embodiments of formulas(II) to (V) or a pharmaceutically acceptable salt thereof, with apharmaceutical carrier or diluent.

In another embodiment, the invention is directed to compounds ofExamples 1—as described herein, or pharmaceutically acceptable saltsthereof.

As used herein, the definitions of each of Q-Y—Z should read from leftto right, so that when Q is ═CR¹⁰—, Y is ═CR¹⁰—CR¹¹═ and Z is ═CR¹⁰—,the formula (I) ring structure should appear as follows:

As used herein, the definitions of X¹-X² are read from left to right, sothat when X¹-X² is —CR¹⁰R¹¹═CR¹²CR¹³—, the formula (I) ring structureshould appear as follows:

As used herein, the term “alkyl,” by itself or as part of anothersubstituent, means a saturated straight or branched chain hydrocarbonradical having the number of carbon atoms designated (e.g., C₁₋₁₀ alkylmeans an alkyl group having from one to ten carbon atoms). Suitablealkyl groups for use in the invention are C₁₋₆ alkyl groups, having fromone to six carbon atoms. Exemplary alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, andthe like.

The term “C₀ alkyl,” for example in the term “—C₀alkyl-C₆₋₁₂ aryl”,refers to a bond.

As used herein, the term “alkenyl,” by itself or as part of anothersubstituent, means a straight or branched chain hydrocarbon radicalhaving a single carbon-carbon double bond and the number of carbon atomsdesignated (e.g., C₂₋₁₀ alkenyl means an alkenyl group having from twoto ten carbon atoms). Suitable alkenyl groups for use in the inventionare C₂₋₆ alkenyl groups, having from two to six carbon atoms. Exemplaryalkenyl groups include ethenyl and propenyl.

Suitable cycloalkyl groups for use in the invention are monocyclic C₃₋₈cycloalkyl groups, having from three to eight carbon atoms. Exemplarymonocyclic cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like. Exemplary bridged cycloalkylgroups include adamantly and norbornyl. Exemplary fused cycloalkylgroups include decahydronaphthalene.

As used herein, the term “heterocyclic,” by itself or as part of anothersubstituent, means a cycloalkyl group as defined above, in which one ormore of the ring carbon atoms is replaced with a heteroatom (such as N,S or O). Suitable non-aromatic heterocyclic groups for use in theinvention include piperidinyl, piperazinyl, morpholinyl,tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, pyrazolidinyl andimidazolildinyl. In certain embodiments, heterocyclic groups for use inthe invention have four to eight ring atoms and a single nitrogen oroxygen heteroatom.

When a heterocyclic group as defined herein is substituted, thesubstituent may be bonded to a ring carbon atom of the heterocyclicgroup, or to a ring heteroatom (i.e., a nitrogen, oxygen or sulfur),which has a valence which permits substitution. Similarly, when aheterocyclic group is defined as a substituent herein, the point ofattachment may be at a ring carbon atom of the heterocyclic group, or ona ring heteroatom (i.e., a nitrogen, oxygen or sulfur), which has avalence which permits attachment.

As used herein, the term “aryl,” by itself or as part of anothersubstituent, means an aromatic or cyclic radical having the number ofcarbon atoms designated (e.g., C₆₋₁₀ aryl means an aryl group havingfrom six to ten carbons atoms). The term “aryl” includes multiple ringsystems (such as fused ring systems) as well as single ring systems, andincludes multiple ring systems wherein part of the molecule is aromaticand part is non-aromatic. A suitable single ring aryl group for use inthe invention is phenyl. Suitable fused ring aryl groups includenaphthyl, tetrahydronaphthyl and indanyl.

The term “halo” or “halogen” includes fluoro, chloro, bromo and iodo.

As used herein, the term “heteroaryl,” by itself or as part of anothersubstituent, means an aromatic cyclic group having at least one ringheteroatom (O, N or S). The term “heteroaryl” includes multiple ringsystems as well as single ring systems. Exemplary heteroaryl groups havefrom 5 to 12 ring atoms. Exemplary heteroaryl groups include pyrazinyl,pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl,furanyl, imidazolyl, indazolyl, triazinyl, pyranyl, thiazolyl, thienyl,triazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, indolyl,quinolinyl, isoquinolinyl, benzimidazolyl, benzofuranyl, indynyl andbenzoxazolyl.

When a heteroaryl group as defined herein is substituted, thesubstituent may be bonded to a ring carbon atom of the heteroaryl group,or on a ring heteroatom (i.e., a nitrogen, oxygen or sulfur), which hasa valence which permits substitution. Similarly, when a heteroaryl groupis defined as a substituent herein, the point of attachment may be at aring carbon atom of the heteroaryl group, or on a ring heteroatom (i.e.,a nitrogen, oxygen or sulfur), which has a valence which permitsattachment.

As used herein, the term “beta-secretase” or “β-secretase” refers to anenzyme that is sometimes known in the literature as “BACE”, “BACE1”(see, e.g., Vassar et al., 1999, Science 286:735-741), or “BACE2” (see,e.g., Farzan et al., 2000, PNAS 97:9712-9717). BACE1 is a 501 amino acidmembrane-bound aspartic protease. BACE1 has all the known functionalproperties and characteristics of β-secretase. BACE2, also called Asp-1or memapsin-1, is a second member of the BACE family of membrane-boundaspartic proteases. See Roggo, Current Topics in Medicinal Chemistry,2002, 2:359-370, for a further discussion of the differences betweenBACE1 and BACE2.

The compounds of the invention are inhibitors of both the BACE1 andBACE2 enzyme.

The compounds of formula (I) have at least one asymmetric center.Additional asymmetric centers may be present depending upon the natureof the various substituents on the molecule.

Compounds with asymmetric centers give rise to enantiomers (opticalisomers), diastereomers (configurational isomers) or both. All of thepossible enantiomers and diastereomers in mixtures (as pure or partiallypurified compounds) are included within the scope of formula (I)

Compounds described herein may contain one or more double bonds, and maythus give rise to cis/trans isomers as well as other configurationalisomers. The compounds of formula (I) include all such possible isomersas well as mixtures of such isomers.

Formula (I) is shown above without a definite stereochemistry at certainpositions. Figure (I) as depicted includes all stereoisomers of formula(I) and pharmaceutically acceptable salts thereof.

The independent syntheses of the enantiomerically or diastereomericallyenriched compounds, or their chromatographic separations, may beachieved as known in the art by appropriate modification of themethodology disclosed herein. Their absolute stereochemistry may bedetermined by the x-ray crystallography of crystalline products orcrystalline intermediates that are derivatized, if necessary, with areagent containing an asymmetric center of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers or diastereomers are isolated. The separationcan be carried out by methods well known in the art, such as thecoupling of a racemic mixture of compounds to an enantiomerically purecompound to form a diastereomeric mixture, followed by separation of theindividual diastereomers by standard methods, such as fractionalcrystallization or chromatography. The coupling reaction is often theformation of salts using an enantiomerically pure acid or base. Thediastereomeric derivatives may then be converted to the pure enantiomersby cleavage of the added chiral residue. The racemic mixture of thecompounds can also be separated directly by chromatographic methodsusing chiral stationary phases, which methods are well known in the art.

Alternatively, any enantiomer or diastereomer of a compound may beobtained by stereoselective synthesis using optically pure startingmaterials or reagents of known configuration by methods well known inthe art.

The term “substantially pure” means that the isolated material is atleast 90% pure, as assayed by analytical techniques known in the art. Inone embodiment, the isolated material is at least 95% pure. In anotherembodiment, the isolated material is at least 99% pure.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. The compoundsof the invention may be mono, di or tris salts, depending on the numberof acid functionalities present in the free base form of the compound.Free bases and salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc, and the like. Particularsalts are the ammonium, calcium, magnesium, potassium, and sodium salts.Salts in the solid form may exist in more than one crystal structure,and may also be in the form of hydrates. Salts derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, and basic ionexchange resins, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine,histidine, hydrabamine, isopropylamine, lysine, methylglucamine,morpholine, piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, and the like. When the compound of the present inventionis basic, salts may be prepared from pharmaceutically acceptablenon-toxic acids, including inorganic and organic acids. Such acidsinclude acetic, trifluoroacetic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.Particular salts are the citric, hydrobromic, hydrochloric,trifluoroacetic, maleic, phosphoric, sulfuric, fumaric, and tartaricacids.

The present invention is directed to the use of the compounds offormulas (I) to (III) disclosed herein as inhibitors of β-secretaseenzyme activity or β-site amyloid precursor protein-cleaving enzyme(“BACE”) activity, in a patient or subject such as a mammal in need ofsuch inhibition, comprising the administration of an effective amount ofthe compound. The terms “-secretase enzyme,” “β-site amyloid precursorprotein-cleaving enzyme,” and “BACE” are used interchangeably in thisspecification. In addition to humans, a variety of other mammals can betreated according to the method of the present invention.

The compounds of the present invention have utility in treating,ameliorating, controlling or reducing the risk of Alzheimer's disease.For example, the compounds may be useful for the prevention of dementiaof the Alzheimer's type, as well as for the treatment of early stage,intermediate stage or late stage dementia of the Alzheimer's type. Thecompounds may also be useful in treating, ameliorating, controlling orreducing the risk of diseases mediated by abnormal cleavage of amyloidprecursor protein (also referred to as APP), and other conditions thatmay be treated or prevented by inhibition of β-secretase. Suchconditions include mild cognitive impairment, Trisomy 21 (DownSyndrome), cerebral amyloid angiopathy, degenerative dementia,Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type(HCHWA-D), Creutzfeld-Jakob disease, prion disorders, amyotrophiclateral sclerosis, progressive supranuclear palsy, head trauma, stroke,pancreatitis, inclusion body myositis, other peripheral amyloidoses,diabetes and atherosclerosis.

The subject or patient to whom the compounds of the present invention isadministered is generally a human being, male or female, in whominhibition of β-secretase enzyme activity is desired, but may alsoencompass other mammals, such as dogs, cats, mice, rats, cattle, horses,sheep, rabbits, monkeys, chimpanzees or other apes or primates, forwhich inhibition of β-secretase enzyme activity or treatment of theabove noted disorders is desired.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment of diseases or conditions forwhich the compounds of the present invention have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone. Additionally, the compounds of the present inventionmay be used in combination with one or more other drugs that treat,prevent, control, ameliorate, or reduce the risk of side effects ortoxicity of the compounds of the present invention. Such other drugs maybe administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with the compounds of the presentinvention. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to the compounds of the present invention. Thecombinations may be administered as part of a unit dosage formcombination product, or as a kit or treatment protocol wherein one ormore additional drugs are administered in separate dosage forms as partof a treatment regimen.

The term “composition” as used herein is intended to encompass a productcomprising specified ingredients in predetermined amounts orproportions, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts. This term in relation to pharmaceutical compositionsis intended to encompass a product comprising one or more activeingredients, and an optional carrier comprising inert ingredients, aswell as any product which results, directly or indirectly, fromcombination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients.

Examples of combinations of the compounds of the present invention withother drugs in either unit dose or kit form include combinations withanti-Alzheimer's agents, for example other beta-secretase inhibitors orgamma-secretase inhibitors; glycine transport inhibitors, tauphosphorylation inhibitors; blockers of Aβ oligomer formation; p25/CDK5inhibitors; HMG-CoA reductase inhibitors; PPAR gamma agonists, such aspioglitazone and rosiglitazone; NK1/NK3 receptor antagonists; NSAID'sincluding ibuprofen; vitamin E; anti-amyloid antibodies, includinganti-amyloid humanized monoclonal antibodies; COX-2 inhibitors;anti-inflammatory compounds, such as (R)-flurbiprofen; CB-1 receptorantagonists or CB-1 receptor inverse agonists; antibiotics such asdoxycycline and rifampin; N-methyl-D-aspartate (NMDA) receptorantagonists, such as memantine and neramexane; NR2B antagonists;androgen receptor modulators; acetylcholinesterase inhibitors such asgalantamine, rivastigmine, donepezil, and tacrine; mGluR5 modulators;growth hormone secretagogues such as ibutamoren, ibutamoren mesylate,and capromorelin; histamine H₃ antagonists; AMPA agonists; PDE IVinhibitors; GABA_(A) inverse agonists; GABA_(A) α 5 receptor ligands;GABA_(B) receptor ligands; potassium channel blockers; neuronalnicotinic agonists; P-450 inhibitors, such as ritonavir; or other drugsthat affect receptors or enzymes that either increase the efficacy,safety, convenience, or reduce unwanted side effects or toxicity of thecompounds of the present invention. The foregoing list of combinationsis illustrative only and not intended to be limiting in any way.

In the pharmaceutical composition the active compound, which is acompound of the invention, is included in an amount sufficient toproduce the desired effect upon the process or condition of diseases.Accordingly, the pharmaceutical compositions of the present inventionencompass any composition made by admixing a compound of the inventionand a pharmaceutically acceptable carrier.

The carrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). Thus, the pharmaceutical compositions of theinvention can be presented as discrete units suitable for oraladministration such as capsules, cachets or tablets each containing apredetermined amount of the active ingredient. Further, the compositionscan be presented as a powder, as granules, as a solution, as asuspension in an aqueous liquid, as a non-aqueous liquid, as anoil-in-water emulsion or as a water-in-oil liquid emulsion. In additionto the common dosage forms set out above, the compounds of theinvention, may also be administered by controlled release means and/ordelivery devices.

Pharmaceutical compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tablets maycontain a compound of the invention in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period.

A tablet containing a composition of this invention may be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets may be prepared bycompressing, in a suitable machine, a compound of the invention in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Incertain embodiments, each tablet contains from about 0.1 mg to about 500mg of the active ingredient and each cachet or capsule contains fromabout 0.1 mg to about 500 mg of the compound of the invention.

Compositions for oral use may also be presented as hard gelatin capsuleswherein the compound of the invention is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the compound of the invention is mixedwith water or an oil medium, for example peanut oil, liquid paraffin, orolive oil.

Other pharmaceutical compositions include aqueous suspensions, whichcontain the active materials in admixture with excipients suitable forthe manufacture of aqueous suspensions. In addition, oily suspensionsmay be formulated by suspending the compound of the invention in avegetable oil, for example arachis oil, olive oil, sesame oil or coconutoil, or in a mineral oil such as liquid paraffin. Oily suspensions mayalso contain various excipients. The pharmaceutical compositions of theinvention may also be in the form of oil-in-water emulsions, which mayalso contain excipients such as sweetening and flavoring agents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension, or in the form of sterilepowders for the extemporaneous preparation of such sterile injectablesolutions or dispersions. In all cases, the final injectable form mustbe sterile and must be effectively fluid for easy syringability. Thepharmaceutical compositions must be stable under the conditions ofmanufacture and storage, and should be preserved against thecontaminating action of microorganisms such as bacteria and fungi.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, or the like. Further, the compositionscan be in a form suitable for use in transdermal devices. Theseformulations may be prepared via conventional processing methods. As anexample, a cream or ointment is prepared by mixing hydrophilic materialand water, together with about 5 wt % to about 10 wt % of the compoundof the invention, to produce a cream or ointment having a desiredconsistency.

Pharmaceutical compositions of this invention can also be in a formsuitable for rectal administration wherein the carrier is a solid.Suitable carriers include cocoa butter and other materials commonly usedin the art.

A “pharmaceutically acceptable excipient,” “pharmaceutically acceptablediluent,” “pharmaceutically acceptable carrier,” and “pharmaceuticallyacceptable adjuvant” means an excipient, diluent, carrier, and adjuvantthat are useful in preparing a pharmaceutical composition that aregenerally safe, non-toxic and neither biologically norotherwise-undesirable, and include an excipient, diluent, carrier, andadjuvant that are acceptable for veterinary use as well as humanpharmaceutical use. “A pharmaceutically acceptable excipient, diluent,carrier and adjuvant” as used in the specification and claims includesboth one and more than one such excipient, diluent, carrier, andadjuvant. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

Optional” or “optionally” means that the subsequently described event,circumstance, feature, or element may, but need not, occur, and that thedescription includes instances where the event or circumstance occursand instances in which it does not. For example, “heterocyclo groupoptionally mono- or di-substituted with an alkyl group” means that thealkyl may, but need not, be present, and the description includessituations where the heterocyclo group is mono- or disubstituted with analkyl group and situations where the heterocyclo group is notsubstituted with the alkyl group.

The terms “administration of” or “administering a” compound should beunderstood to mean providing a compound of the invention to theindividual in need of treatment in a form that can be introduced intothat individual's body in a therapeutically useful form andtherapeutically useful amount, including, but not limited to: oraldosage forms, such as tablets, capsules, syrups, suspensions, and thelike; injectable dosage forms, such as IV, IM, or IP, and the like;transdermal dosage forms, including creams, jellies, powders, orpatches; buccal dosage forms; inhalation powders, sprays, suspensions,and the like; and rectal suppositories.

The terms “effective amount” or “therapeutically effective amount” meansthe amount of the subject compound that will elicit the biological ormedical response of a tissue, system, animal or human that is beingsought by the researcher, veterinarian, medical doctor or otherclinician.

As used herein, the term “treatment” or “treating” means anyadministration of a compound of the invention to obtain a desiredpharmacologic and/or physiologic effect. The effect may be prophylacticin terms of completely or partially preventing a disease or symptomthereof, and/or may be therapeutic in terms of a partial or completecure for a disease and/or adverse affect attributable to the disease.Treatment includes (1) inhibiting the disease in an animal that isexperiencing or displaying the pathology or symptomatology of thediseased (i.e., arresting further development of the pathology and/orsymptomatology), or (2) ameliorating the disease in an animal that isexperiencing or displaying the pathology or symptomatology of thediseased (i.e., reversing the pathology and/or symptomatology).

The terms “individual,” “subject,” and “patient,” used interchangeablyherein, refer to a mammal, including, but not limited to, murines,simians, humans, mammalian farm animals, mammalian sport animals, andmammalian pets.

The compositions containing compounds of the invention may convenientlybe presented in unit dosage form and may be prepared by any of themethods well known in the art of pharmacy.

The term “unit dosage form” is taken to mean a single dose wherein allactive and inactive ingredients are combined in a suitable system, suchthat the patient or person administering the drug to the patient canopen a single container or package with the entire dose containedtherein, and does not have to mix any components together from two ormore containers or packages. Typical examples of unit dosage forms aretablets or capsules for oral administration, single dose vials forinjection, or suppositories for rectal administration. This list of unitdosage forms is not intended to be limiting in any way, but merely torepresent typical examples of unit dosage forms.

Before the present invention is further described, it is to beunderstood that this invention is not limited to particular embodimentsdescribed, as such may, of course, vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present invention will be limited only by the appendedclaims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges, and are also encompassed within the invention, subjectto any specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, the preferredmethods and materials are now described. All publications mentionedherein are incorporated herein by reference to disclose and describe themethods and/or materials in connection with which the publications arecited.

It must be noted that as used herein and in the appended claims, thesingular forms “a,” “and,” and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimsmay be drafted to exclude any optional element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

Publications discussed herein are provided solely for their disclosureprior to the filing date of the present application. Nothing herein isto be construed as an admission that the present invention is notentitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.

The compositions containing compounds of the invention may convenientlybe presented as a kit, whereby two or more components, which may beactive or inactive ingredients, carriers, diluents, and the like, areprovided with instructions for preparation of the actual dosage form bythe patient or person administering the drug to the patient. Such kitsmay be provided with all necessary materials and ingredients containedtherein, or they may contain instructions for using or making materialsor components that must be obtained independently by the patient orperson administering the drug to the patient.

When treating, ameliorating, controlling or reducing the risk ofAlzheimer's disease or other diseases for which compounds of theinvention are indicated, generally satisfactory results are obtainedwhen the compounds of the invention are administered at a daily dosageof from about 0.1 mg to about 100 mg per kg of animal body weight. Forexample, the compounds may be given as a single daily dose or in divideddoses two to six times a day, or in sustained release form. The totaldaily dosage is from about 1.0 mg to about 2000 mg (for example, fromabout 0.1 mg to about 20 mg per kg of body weight). In the case of a 70kg adult human, the total daily dose will generally be from about 7 mgto about 1,400 mg. This dosage regimen may be adjusted to provide theoptimal therapeutic response. The compounds may be administered on aregimen of 1 to 4 times per day, for example once or twice per day.

The amount of the compound of the invention that may be combined withthe carrier materials to produce a single dosage form will varydepending upon the host treated and the particular mode ofadministration. For example, a formulation intended for the oraladministration to humans may conveniently contain from about 0.005 mg toabout 2.5 g of a compound of the invention, compounded with anappropriate and convenient amount of carrier material. Unit dosage formswill generally contain between from about 0.005 mg to about 1000 mg ofthe compound of the invention, typically 0.005 mg, 0.01 mg, 0.05 mg,0.25 mg, 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500mg, 600 mg, 800 mg or 1000 mg, administered once, twice or three times aday.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

The compounds of the invention may be prepared according to thefollowing reaction Schemes, in which variables are as defined before orare derived, using readily available starting materials, from reagentsand conventional synthetic procedures. It is also possible to usevariants which are themselves known to those of ordinary skill inorganic synthesis art, but are not mentioned in greater detail.

The present invention also provides a method for the synthesis ofcompounds useful as intermediates in the preparation of compounds of theinvention.

Generic scheme I outlines a method for preparing compounds havingdifferent combination of 4-spiro fused aryl and amide substituents onthe pyrrolidine ring. In this method, the appropriate cyclic ketone A isreacted with triethylphosphonoacetate to yield upon isolation thedesired E-stereoisomer B which undergoes dipolar cycloaddition upontreatment with benzyl-N-(methoxymethyl)-trimethylsilylmethyl amine as anazomethine ylide precursor to provide the trans pyrrolidine C. The esteris hydrolyzed and coupled under standard conditions with a suitableamine E. Removal of the benzyl amine by either hydrogenation or otherchemical methods such as a-chloroethyl chloroformate yields the targetproducts F.

Generic Scheme II outlines a method for preparing 4-spirofused compoundsthat have a spiro ring substitution that is not compatible withhydrogenation conditions. In this method, the appropriate ketone isreacted with triethylphosphonoacetate to yield upon isolation thedesired E-stereoisomer Bb which undergoes dipolar cycloaddition upontreatment with benzyl-N-(methoxymethyl)-trimethylsilylmethyl amine as anazomethine ylide precursor to provide the trans pyrrolidine Cc. Thebenzyl protecting group is then exchanged for a t-butoxycarbonyl bysequential treatment with 1-chloroethyl chloroformate, then methanol,and finally BOC anhydride to provide the BOC-protected pyrrolidine Dd.The ester is hydrolyzed and coupled under standard conditions with asuitable amine. TFA mediated deprotection of the t-butyl carbamateyields the desired product Ff.

Intermediate I: (2S,4R)-2-cyclohexyl-4-phenylpiperidine

Step 1: Benzyl 2-cyclohexyl-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate

4-methoxypyridine (17.56 ml, 173 mmol) in THF (577 ml) at −30° C. wasadded benzyl chloroformate (24.70 ml, 173 mmol) dropwise. Stirred at−30° C. for 30 minutes and then added cyclohexylmagnesium chloride (200ml, 260 mmol). Stirred for 30 minutes at −30° C. and quenched with 1NHCl. Extracted 3 times with diethyl ether. The combined organicfractions were combined, dried (Na_(z) SO₄), filtered and the solventwas evaporated under reduced pressure. Purified on silica gel 30%EtOAc/Hexanes affording 35.25 g.

¹H NMR (CDCl₃) δ 7.83 (br s, 1H), 7.42-7.36 (m, 5H), 5.34-5.24 (m, 3H),4.38 (br s, 1H), 2.80-2.72 (m, 1H), 2.66-2.58 (m, 1H), 1.77-1.42 (m,6H), 1.17-0.91 (m, 5H).

Step 2: Benzyl 2-cyclohexyl-4-oxopiperidine-1-carboxylate

Benzyl 2-cyclohexyl-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (35.25g, 112 mmol) was dissolved in AcOH (450 ml) and added zinc dust (22.07g, 337 mmol). The solution stirred at room temperature for 12 hours. Thesolution was filtered through celite and washed with EtOAc. The solventwas evaporated under reduced pressure and the product was purified bycolumn chromatography on silica gel 30% EtOAc/Hexanes.

¹H NMR (CDCl₃) δ 7.40-7.31 (m, 5H), 5.22-5.14 (m, 2H), 4.54-4.21 (m,2H), 3.19-3.08 (m, 1H), 2.62-2.43 (m, 3H), 2.35-2.27 (m, 1H), 1.82-1.53(m, 6H), 1.42-0.80 (m, 5H).

Step 3: Benzyl 2-cyclohexyl-4-hydroxy-4-phenylpiperidine-1-carboxylate

Benzyl 2-cyclohexyl-4-oxopiperidine-1-carboxylate in THF (155 ml) wascooled to 0° C. and added phenylmagnesium bromide (22.08 ml, 61.8 mmol).The ice bath was removed and the solution stirred at room temperaturefor 14 hours. Quenched the reaction with 1N HCl and concentrated.Extracted three times with EtOAc and washed twice with water. Theorganics were dried, concentrated, and purified on silica gel 30% EtOAc.

¹H NMR (CDCl₃) δ 7.47-7.43 (m, 2H), 7.38-7.24 (m, 8H), 5.16 (s, 2H),4.25-3.92 (m, 2H), 3.40-3.27 (m, 1H), 2.38-2.27 (m, 1H), 2.15-2.04 (m,1H), 1.92-1.84 (m, 2H), 1.79-1.62 (m, 5H), 1.33-1.08 (m, 4H), 0.98-0.82(m, 3H).

Step 4: Benzyl2-cyclohexyl-4-phenyl-3,6-dihydropyridine-1(2H)-carboxylate

A solution of BF₃.OEt₂ (4.93 ml, 38.9 mmol) in CH₂Cl₂ (30 ml) was addedto a stirred solution of benzyl2-cyclohexyl-4-hydroxy-4-phenylpiperidine-1-carboxylate (5 g, 12.71mmol) in CH₂Cl₂ (244 ml) at 0° C. The mixture was stirred at roomtemperature for 15 minutes. Saturated sodium bicarbonate (100 ml) wasadded after 15 minutes. Extracted twice with CH₂Cl₂ and the combinedorganics were dried and concentrated. The crude product was notpurified.

¹H NMR (CDCl₃) δ 7.40-7.22 (m, 10H), 6.21-5.93 (m, 1H), 5.22-5.16 (m,2H), 4.58-4.10 (m, 2H), 3.74-3.05 (m, 1H), 2.67-2.32 (m, 2H), 1.88-1.55(m, 6H), 1.27-0.90 (m, 5H).

Step 5: 2-cyclohexyl-4-phenylpiperidine

Benzyl 2-cyclohexyl-4-phenyl-3,6-dihydropyridine-1(2H)-carboxylate (4.7g, 12.52 mmol) in EtOH (25 ml) was added Pd/C (1.18 g, 0.554 mmol) andhydrogenated with a balloon for 10 hours. Filter through celite andconcentrate. The crude piperidine was not purified. LRMS (M+H)=217.10

Step 6: Benzyl 2-cyclohexyl-4-phenylpiperidine-1-carboxylate

2-cyclohexyl-4-phenylpiperidine (2.85 g, 11.71 mmol) in CH₂Cl₂ (58.5 ml)was added benzyl chloroformate (2.507 ml, 17.56 mmol) and triethylamine(2.45 ml, 17.56 mmol). The reaction was stirred at room temperature for2 hours. Added water and extracted 3 times with CH₂Cl₂. The combinedorganics were dried, concentrated, and purified on silica gel 20%EtOAc/Hexanes. Separated cis and trans on the AD column, 20% IPA/Hexanesw/DEA. Peak 1 corresponds to the cis racemic mixture with one transdiastereomer and peak2 is a single trans diastereomer. Obtained 2.5 gracemic cis/trans peak1. Resolved on the OJ column 20% EtOH/Hexanesw/DEA: Peak 1: 0.68 g pure cis undesired, peak 2 1.75 g cis/transmixture.

¹H NMR (CDCl₃) δ 7.39-7.27 (m, 7H), 7.22-7.17 (m, 3H), 5.22-5.14 (m,2H), 4.04-3.97 (m, 1H), 3.90-3.83 (m, 1H), 3.18-3.09 (m, 1H), 2.72-2.61(m, 1H), 2.23-2.12 (m, 1H), 1.97-1.90 (m, 1H), 1.74-1.55 (m, 8H),1.18-0.96 (m, 5H). LRMS (M+H)=378.99

Step 7: (2S,4R)-2-cyclohexyl-4-phenylpiperidine

Benzyl 2-cyclohexyl-4-phenylpiperidine-1-carboxylate (1.05 g, 2.78 mmol)in EtOH (50 ml) was added Pd/C (0.5 g, 0.235 mmol) and hydrogenated witha balloon overnight. Filtered through celite and concentrated. The transisomer was removed on the chiral OD column 20% IPA/Hexanes w/DEAaffording the single cis diastereomer.

¹H NMR (CDCl₃) δ 7.26-7.18 (m, 5H), 3.29-3.23 (m, 1H), 2.82-2.74 (m,1H), 2.65-2.55 (m, 1H), 2.46-2.39 (m, 1H), 1.93-1.87 (m, 2H), 1.85-1.70(m, 5H), 1.66-1.53 (m, 2H), 1.38-0.97 (m, 7H).

LRMS (M+H)=244.05

Intermediate II: (2S,4R)-2-(3,3-Difluorocyclohexyl)-4-phenylpiperidine

Step 1: 3-Oxocyclohex-1-en-1-yl trifluoromethanesulfonate

To a solution of 1 (50 g, 0.48 mmol) and 1,6-lutidine (103 g, 0.96 mmol)in 1 L of dry DCM was added Tf₂O (144 ml, 0.72 mmol) dropwise slowly at0° C. The reaction mixture was stirred at 0° C. for 30 min, warmed toroom temperature, stirred for 1 hour, and quenched with HCl (2.0 N). Themixture was partitioned between DCM and diluted aqueous HCl. The organiclayer was washed with water and brine, dried over anhydrous sodiumsulfate, filtered, and concentrated in vacuo. Purification on silica gelafforded 2 as brown liquid (99 g, 85%).

Step 2:3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-one

To a solution of 2 (55 g, 0.227 mol) and bis-pinacolatodiboron (55.5 g,0.250 mol) in 600 ml of dry dioxane was added K₂CO₃ (47 g, 0.341 mol),followed by Pd(PPh₃)Cl₂ (2.9 g, 6.8 mmol), PPh₃ (3.6 g, 13.6 mmol) undernitrogen. The mixture was refluxed for 4 hour, cooled to roomtemperature, and filtered. The filtrate was used in the next stepdirectly.

Step 3: 3-(4-Phenylpyridin-2-yl)cyclohex-2-en-1-one

To a solution 3 (prepared above) in 800 ml of dioxane were added K₃PO₄(118 g, 0.561 mol), 2-chloro-4-phenylpyridine (35.5 g, 0.187 mol), andPd(dppf)Cl₂ (6 g, 5.6 mmol). The suspension was stirred at 80° C.overnight, filtered, and concentrated in vacuo. Purification on silicagel afforded 4 as a yellow solid (30 g, 64%).

Step 4: 3-(4-Phenylpyridin-2-yl)cyclohexanone

A suspension of 4 (30 g, 0.12 mol) and 2 g of Pd—C in 500 ml of ethylacetate was hydrogenated under 20 psi of pressure of hydrogen at roomtemperature overnight. Filtration and concentration afforded crude of 5as a brown oil (30 g, 100%).

Step 5: 2-(3,3-Difluorocyclohexyl)-4-phenylpyridine

To a solution of DAST (213 g, 1.325 mol) in 500 ml of dry DCM was addeda solution of 5 (52 g, 0.207 mmol) in 500 ml of DCM at −70° C. After 1hour, the reaction mixture was warmed to room temperature slowly, andstirred overnight. The reaction was quenched by adding water slowly at0° C., neutralized with bicarbonate to pH=7-8, and extracted with DCM.The combined organic layers were washed with water and brine, dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo.Purification on silica gel afforded 6 as a yellow liquid (18 g, 32%).

Step 6: 2-(3,3-Difluorocyclohexyl)-1-methyl-4-phenylpyridinium iodide

A mixture of 6 (18 g, 66 mmol) and CH₃I (105 ml, 198 mmol) in CH₃COCH₃(150 ml) in a retort was stirred at 90 degree for 2 days. After cooledto room temperature, the mixture was filtered. The filtered cake waswashed with ethyl acetate to give 7 as a yellow solid (23 g, 85%).

Step 7: 2-(3,3-Difluorocyclohexyl)-1-methyl-4-phenylpiperidine

The suspension of 7 (1.3 g, 3.1 mmol) and PtO₂ (0.26 g) in 50 ml of MeOHwas stirred under 1 atmosphere of hydrogen at room temperatureovernight, and then filtered. The PtO₂ (0.13 g) was added again and thestirring was continued overnight more. After filtered and concentrated,the residue was dissolved in EA and washed with sat. bicarbonate sodium,water, brine, dried over sodium sulfate anhydrous. After filtered andconcentrated, 8 (780 mg, 85%) was obtained as a brown oil.

Step 8: 2-(3,3-Difluorocyclohexyl)-4-phenylpiperidine-1-carbonitrile

To a solution of 8 (780 mg, 2.7 mmol) in 30 ml of CHCl₃ was added K₂CO₃(1.3 g, 8.2 mmol) under nitrogen, followed by BrCN (430 mg, 4.1 mmol).The suspension was refluxed overnight. After cooled to room temperature,the reaction mixture was partitioned between DCM and water. The organiclayer was washed with brine, dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo. Purification on silica gel afforded9 as off-white solid (480 mg, 56%).

Step 9: 2-(3,3-Difluorocyclohexyl)-4-phenylpiperidine

The suspension of 9 (480 mg, 1.6 mmol) in 30 ml of diluted aqueous HCl(1N) was refluxed overnight, and concentrated in vacuo. The residue wasdissolved in ethyl acetate, washed with saturated aqueous NaHCO₃, water,brine, dried over sodium sulfate, filtered, and concentrated in vacuo togive 10 as a colorless oil (400 mg, 91%).

Step 10: Benzyl(2S,4R)-2-(3,3-difluorocyclohexyl)-4-phenylpiperidine-1-carboxylate

To a solution of 10 (4.1 g crude, 14.7 mmol) in 100 ml of THF and 50 mlof water was added sodium carbonate (3.9 g, 36.7 mmol), followed byCbzCl (5 g, 29.4 mmol) at room temperature. The reaction mixture wasstirred at room temperature overnight, diluted with ethyl acetate,washed with water, brine, dried over anhydrous sodium sulfate, filtered,and concentrated in vacuo. Purification on silica gel afforded benzyl2-(3,3-difluorocyclohexyl)-4-phenylpiperidine-1-carboxylate as a mixtureof 4 isomers (2.3 g, 38%). Chiral SFC separation afforded 500 mg ofbenzyl(2S,4R)-2-(3,3-difluorocyclohexyl)-4-phenylpiperidine-1-carboxylate 11.

Step 11: (2S,4R)-2-(3,3-difluorocyclohexyl)-4-phenylpiperidine

A suspension of 11 (500 mg, 1.2 mmol) and Pd(OH)₂ (0.2 g) in 10 ml ofEtOH was hydrogenated under 1 atmosphere of hydrogen at room temperatureovernight. Filtration and concentration afforded(2S,4R)-2-(3,3-difluorocyclohexyl)-4-phenylpiperidine as a colorless oil(330 mg, 98%).

Alternative Procedures for the Preparation of Intermediate II Step 1:tent-Butyl 2-(3-oxocyclohexyl)-4-phenylpiperidine-1-carboxylate

To a solution of compound 1 (10.8 g, 41.2 mmol) in Et₂O (150 mL) at −78°C. was added TMEDA (6.2 mL, 41.2 mmol), followed by sec-BuLi (41.4 mL,1.3 eq, 53.8 mmol). The mixture was stirred at −78° C. for 2 h before asolution of CuCN.2LiCl (3.6 g, 20.6 mmol) in THF (41.2 mL) was added.The reaction mixture was allowed to stir at −50° C. for 1 h before asolution of compound 2 (4 g, 41.2 mmol) in TMSCl (26 mL, 206 mmol) wasadded. The reaction mixture was stirred at −50° C. for 30 min and thenwas allowed to stir at room temperature overnight. The reaction mixturewas quenched with H₂O, stirred at room temperature briefly, diluted withEA, and filtered through Celite. The organic phase was separated, andthe aqueous phase was extracted with EA (40 mL×4). The combined organicphases were washed with saturated NH4Cl (aq.), 5% NaHCO₃ (aq.), brine,and dried over a mixture of anhydrous Na₂SO₄ and K₂CO₃. Evaporation ofthe solvent in vacuo afforded the crude product which was purified bycolumn chromatography to give 6.8 g of compound 3 in 46% yields.

¹H NMR (400 MHz, CDCl₃): δ 7.34 (t, J=7.2 Hz, 2H), 7.23 (t, J=7.2 Hz,3H), 4.31˜4.35 (m, 1H), 4.15˜4.20 (m, 1H), 2.75˜3.0 (m, 2H), 2.25˜2.53(m, 4H), 1.60˜2.25 (m, 8H), 1.25˜1.59 (m, 10H). LRMS (M+Na⁺): 380.

Step 2: 3-(4-Phenylpiperidin-2-yl)cyclohexanone

To a solution of 3 (6.27 g, 17.6 mmol) in MeOH (20 mL) was addedHCl/MeOH (2 M, 40 mL). After 2 hours, the reaction mixture wasconcentrated to give 5.1 g of compound 4 as HCl salt in 100% yields.

LRMS (M+H⁺): 258.

Step 3: Benzyl 2-(3-oxocyclohexyl)-4-phenylpiperidine-1-carboxylate

To a solution of compound 4 (5.1 g, 17.6 mmol) in DCM (50 mL) were addedEt₃N (5.3 g, 52.7 mmol) and CbzCl (4.5 g, 26.3 mmol) at 0° C. Themixture was allowed to stir at room temperature for 2 h, and quenchedwith H₂O, extracted with DCM (20 mL×3). The combined organics werewashed with brine, dried over Na₂SO₄ and concentrated. The residue waspurified by column chromatography to give 5.56 g of compound 5 in 81%yields.

¹H NMR (400 MHz, CDCl₃): δ 7.28˜7.39 (m, 7H), 7.15˜7.23 (m, 3H),5.13˜5.19 (m, 2H), 3.95˜4.45 (m, 2H), 2.60˜3.20 (m, 2H), 1.59˜2.41 (m,13H). LRMS (M+H⁺): 392.

Step 4: Benzyl(2S,4R)-2-(3,3-difluorocyclohexyl)-4-phenylpiperidine-1-carboxylate

To a solution of compound 5 (5.56 g, 14.2 mmol) in DCM (70 mL) was addeddropwise DAST (4 eq, 56.8 mmol) at 0° C. The reaction mixture wasstirred at room temperature for 12 h, poured slowly onto ice-water,extracted with DCM (20 mL×3). The combined organics were washed withNaHCO₃ (aq.) and brine, dried over Na₂SO₄, filtered, and concentrated.The residue was purified by p-HPLC to give 3.64 g of benzyl2-(3,3-difluorocyclohexyl)-4-phenylpiperidine-1-carboxylate in 62%yields as a mixture of 4 isomers.

LRMS (M+H⁺): 414.

The mixture was resolved by SFC column to give benzyl(2S,4R)-2-(3,3-difluorocyclohexyl)-4-phenylpiperidine-1-carboxylate 6.(Column: Chiralcel OJ-H 250*4.6 mm I.D., Sum; Mobile phase: methanol(0.05% DEA) in CO₂ from 5% to 40%; Flow rate: 2.5 mL/min; Wavelength:220 nm).

Step 5: (2S,4R)-2-(3,3-difluorocyclohexyl)-4-phenylpiperidine

A mixture of compound 6 (130 mg, 0.31 mmol) and Pd (OH)₂ (70 mg) in MeOH(20 mL) was stirred at 50° C. under H₂ (50 psi) for 4 hours. The mixturewas filtrated and the filtrate was concentrated to give 80 mg of(2S,4R)-2-(3,3-difluorocyclohexyl)-4-phenylpiperidine 7 in 92% yields.

LRMS (M+H⁺): 280.

Intermediate III: 4-phenyl-2-(2,2,2-trifluoroethyl)piperidine

Step 1: 2-Chloro-4-phenylpyridine

To a mixture of 1 (57.36 g, 0.24 mol) in THF/H₂O (400 mL/100 mL) wereadded phenylboric acid (24.2 g, 0.2 mol) and K₂CO₃ (82.8 g, 0.6 mol).PdCl₂(dppf) (2 g) was then added after being charged with N₂ threetimes. The resulting mixture was refluxed for 2 hrs, cooled, andpartitioned between a.q. NH₄Cl and EtOAc. The aqueous layer was washedwith EtOAc. The combined organic layers were washed with water, brineand dried over Na₂SO₄. The solvent was removed in vacuo and the residuewas purified by silica gel column (PE:EA=10:1) to afford 32 g of 2(yield 84%).

Step 2: Methyl 4-phenylpyridine-2-carboxylate

To a solution of 2 (2 g, 0.01 mol) in MeOH (100 mL) were added TEA (5.33g, 0.05 mol) and PdCl₂(dppf) (0.5 g). The reaction mixture was stirredovernight at 70° C. under 4 MPa CO. The suspension was filtered througha pad of celite and washed with MeOH. The combined filtrates wereconcentrated in vacuo. Purification on silica gel (PE:EA=10:1) afforded1.5 g of 3 (yield 71%).

¹H-NMR (400 MHz, CDCl₃) δ 8.72 (d, 1H), 8.31 (m, 1H), 7.63 (m, 3H), 7.42(m, 3H), 3.95 (s, 3H)

Step 3: (4-Phenylpyridin-2-yl)methanol

To a solution of 3 (1.5 g, 7 mmol) in THF (20 mL) was added LiAlH4 (0.32g, 8.4 mmol). The reaction mixture was stirred at room temperature for30 minutes, quenched by adding 15% NaOH aqueous solution, and filteredthrough silica gel. The filtrate was concentrated to give the crudeproduct, which was used directly in the next step without furtherpurification.

Step 4: 4-Phenylpyridine-2-carbaldehyde

To a solution of 4 (1.4 g, 7 mmol) in CH₂Cl₂ (100 mL) was added MnO₂(1.8 g, 21 mmol). The mixture was refluxed overnight, cooled, andfiltered through silica gel. The filtrate was concentrated in vacuo.Purification on silica gel (PE:EA=10:1) afforded 1.1 g of 5 (yield 78%).

¹H-NMR (400 MHz, CDCl₃) δ 10.14 (s, 1H), 8.82 (d, 1H), 8.18 (m, 1H),7.64 (m, 3H), 7.45 (m, 3H)

Step 5: 2,2,2-Trifluoro-1-(4-phenylpyridin-2-yl)ethanol

To the solution of TMSCF₃ (245 mg, 2.5 mmol) in THF (50 mL) were added 5(366 mg, 2 mmol) and TBAT (cat). The reaction mixture was stirred atroom temperature for 1 hr before 1.0 N HCl (5 mL) was added. After 1 hr,the reaction mixture was partitioned between aqueous NaHCO₃ and EtOAc.The aqueous layer was washed with EtOAc. The combined organic layerswere washed with water and brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product thus obtained was used directlyin the next step without further purification.

¹H-NMR (400 MHz, CDCl₃) δ 8.62 (d, 1H), 7.25-7.61 (m, 8H), 5.05 (m, 1H),

Step 6: 4-Phenyl-2-(2,2,2-trifluoroethyl)pyridine

A mixture of 6 (647 mg, 2.9 mmol), NaH (232 mg, 5.8 mmol, 60% in mineraloil), imidazole (26 mg, 0.3 mmol) in THF (30 mL) was stirred for a halfan hour at room temperature before CS₂ (2 mL, 33.3 mmol) was introduced.After stirring for 1 h, iodomethane (0.3 mL, 4.8 mmol) was added. Theresultant reaction mixture was stirred for another hour, poured intowater (30 mL), extracted with EtOAc two times. The combined organiclayers were washed with water and brine, dried over Na2SO4, filtered,and concentrated in vacuo to give a yellow oil. The residue wasdissolved in toluene (30 mL), to which catalytic AIBN (100 mg) wasadded. The reaction mixture was refluxed under N₂ while a solution ofBu₃SnH (3 mL, 11 mmol) in toluene (3 mL) was added slowly over 30minutes. After refluxing overnight, the reaction mixture was cooled,partitioned between saturated NaHCO₃ aqueous solution and EtOAc. Thecombined organic layers were washed with water and brine, dried overNa₂SO₄. The solvent was removed in vacuo and the residue was purified bysilica gel column (PE:EA=20:1) to afford 0.32 g of 7 (yield 53%).

Step 7: 4-phenyl-2-(2,2,2-trifluoroethyl)piperidine

To a solution of 7 (300 mg, 1.23 mmol) in acetic acid (10 mL) was addedPd/C (100 mg). The reaction mixture was hydrogenated at 80° C. for 2hrs. LC-MS showed the starting material was consumed. The suspension wasfiltered through a pad of celite and washed with methanol. The combinedfiltrates were concentrated in vacuo. The residue was partition betweenaqueous NaHCO₃ and EtOAc. The separated aqueous layer was washed withEtOAc. The combined organic layers were washed with water, brine anddried over Na₂SO₄. The solvent was removed in vacuo to afford4-phenyl-2-(2,2,2-trifluoroethyl)piperidine 8.

Intermediate A to YY are depicted below in Table 1. Intermediates A toYY are either commercially available, or are taught in the literature.

TABLE 1 INTERMEDIATE STRUCTURE SOURCE A

Commercially available B

Commercially available C

Commercially available D

Commercially available E

Commercially available F

Commercially available G

Commercially available H

Commercially available I

Organic Letters (2005), 7(23), 5167-5170 J

Synlett (2007), (11), 1699-1702 K

Commercially available L

US 2005043309 M

J Heterocyclic Chemistry (2000), 37(1), 41-46 N

Commercially available O

Commercially available P

Synthesis 1983, 11, 902-903 Q

Synthesis 1983, 11, 902-903 R

Commercially available S

Commercially available T

J. Med. Chem., 1974, 17(9), 1020-1023 U

J. Org. Chem., (1985), 50(12), 2128- 2133 V

Commercially available W

Bulletin Chem Soc Japan (1999), 72(2), 303-311 X

Chem Communications (2007), 44: 4686-4688 Y

Commercially available Z

Commercially available AA

Heterocycles (1986), 24(9); 2011-2618. BB

Indian Journmal of Chem., Section B: Organic Chemistry (1985), 24B(6),659-661. CC

J. Labelled Compounds and Radiopharma- ceuticals (1990), 28(1), 15-24.DD

WO 2005/005438 EE

J. Heterocyclic Chem. (1975), 9(1), 44-48. FF

Tetrahedron Letters (1986), 27(10), 1127-1130. GG

Eur. J. Med. Chem. (2000), 39(9), 815-823. HH

J. Org. Chem. (1990), 55(16), 4789-4791. II

U.S. Pat. No. 4,952,694 JJ

J. Chem. Soc. Perkin Trans. (1985), (2), 213-219. KK

U.S. Pat. No. 3,998,331 LL

Arch. Pharma. (1985), 318(10), 871-878. MM

J. Med Chem. (1977), 20(5), 718-721. NN

J. Heterocyclic Chem., 1983, 649. OO

WO 2006/047017 PP

Heterocycles, 1997, 129. QQ

J. Am. Chem. Soc. (1985), 107(17), 4998-4999. RR

J. Am. Chem. Soc. (1985), 107(17), 4998-4999. SS

Heterocycles (1995), 41(1), 29- 36. TT

J. Prak. Chemie (1999), 341(5), 487-491. UU

J. Med. Chem. (1990), 33(11), 3028-3034.. VV

Commercially available WW

WO 98/00134 XX

Commercially available YY

J. Org. Chem. (2002), 67(11), 3972-3974.

Example 14′-[(4-phenylpiperidin-1-yl)carbonyl]-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidine]

Step 1: Ethyl(2E)-3,4-dihydronaphthalen-1(2H)-ylideneacetate

Sodium hydride (2.160 g, 54.0 mmol) in THF (150 ml) was added triethylphosphonoacetate (10.81 ml, 54.0 mmol) dropwise. Stir at roomtemperature for 1 hour, added a-tetralone (3.99 ml, 30 mmol) and heatedovernight at 70° C. The next day the solution was cooled to roomtemperature and quenched with 1N HCl. Extracted three times with EtOAcand washed the combined organics with brine. The organics were driedover sodium sulfate, concentrated, and purified on silica gel 10%EtOAc/Hex.

¹H NMR (CDCl₃) δ 7.65 (d, J=7.9 Hz, 1H), 7.27-7.13 (m, 3H), 6.33 (t,J=1.8 Hz, 1H), 4.20 (q, J=7.1 Hz, 2H), 3.22-3.17 (m, 2H), 2.80 (t, J=6.2Hz, 2H), 1.88-1.83 (m, 2H), 1.32 (t, J=7.1 Hz, 3H). LRMS (M+H)=217.10

Step 2: Ethyl1′-benzyl-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidine]-4′-carboxylate

N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (2.112 ml, 8.26mmol) and ethyl(2E)-3,4-dihydronaphthalen-1(2H)-ylideneacetate (1.785 g,8.26 mmol) in CH₂Cl₂ (33.3 ml) at 0° C. was added TFA (0.064 ml, 0.826mmol) dropwise. Removed the ice bath and stirred at room temperature for4 hours. Dilute with CH₂Cl₂ and wash twice with saturated NaHCO₃. Theorganics were dried over sodium sulfate, concentrated, and purified onsilica gel 20% EtOAc/Hex.

¹H NMR (CDCl₃) δ 7.76-7.68 (m, 1H), 7.41-7.18 (m, 6H), 7.15-7.09 (m,1H), 7.06-6.98 (m, 1H), 4.12-4.03 (m, 2H), 3.75-3.63 (m, 2H), 3.42-3.36(m, 1H), 3.20-3.10 (m, 1H), 3.07-2.90 (m, 2H), 2.78-2.67 (m, 2H),2.63-2.57 (m, 1H), 1.89-1.81 (m, 2H), 1.69-1.62 (m, 2H), 1.20-1.09 (m,3H).

LRMS (M+H)=350.20

Step 3:1′-benzyl-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidine]-4′-carboxylicacid

Ethyl1′-benzyl-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidine]-4′-carboxylate(1.1 g, 3.15 mmol) in THF/MeOH/H2O (41 ml) was added 2N sodium hydroxide(4.72 ml, 9.44 mmol). Stir overnight at 50° C. Cooled to roomtemperature and acidified to pH1-2 with 0.5N HCl and extracted withEtOAc. The organic layer was dried and concentrated. The crude acid wasnot purified.

¹H NMR (CDCl₃) δ 7.36-7.22 (m, 6H), 7.11-6.92 (m, 3H), 3.73-3.65 (m,2H), 3.18-3.11 (m, 2H), 3.00-2.49 (m, 6H), 1.89-1.55 (m, 3H). LRMS(M+H)=322.08

Step 4:N-benzyl-4′-[(4-phenylpiperidin-1-yl)carbonyl]-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidine]

N-benzyl-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidine]-4′-carboxylicacid (0.1 g, 0.311 mmol) in CH₂Cl₂ (4 ml) was added oxalyl chloride(0.187 ml, 0.373 mmol) followed by 2 drops of DMF. Stirred at roomtemperature for 30 minutes and concentrated. Dissolve in THF (5 mL) andadded 4-phenylpiperidine (0.050 g, 0.311 mmol) and triethylamine (0.173ml, 1.245 mmol).

The solution was stirred for 2 hours then concentrated, taken up inCH₂Cl₂ and washed with water. The crude product was not purified.

¹H NMR (CDCl₃) δ 7.86-7.78 (m, 1H), 7.40-7.35 (m, 2H), 7.31-7.16 (m,7H), 7.10-7.03 (m, 3H), 7.00-6.95 (m, 1H), 4.88-4.73 (m, 1H), 3.72-3.55(m, 4H), 3.29-3.08 (m, 5H), 2.76-2.69 (m, 3H), 2.60-2.39 (m, 4H),2.10-2.02 (m, 1H), 1.80-1.60 (m, 4H). LRMS (M+H)=465.22

Step 5:4′-[(4-phenylpiperidin-1-yl)carbonyl]-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidine]

N-benzyl-4′-[(4-phenylpiperidin-1-yl)carbonyl]-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidine](0.15 g, 0.323 mmol) in EtOH (20 ml) was added Pearlman's Catalyst(0.075 g, 0.107 mmol) and hydrogenated with a balloon for 2 hours.Filtered through celite and concentrated.

The product was purified on the Waters Prep HPLC. The desired fractionswere free based with NaHCO₃ and extracted 2× with EtOAc.

¹H NMR (CD₃OD) δ 7.67-7.54 (m, 1H), 7.30-7.08 (m, 6H), 6.96-6.91 (m,2H), 4.66-4.57 (m, 1H), 4.17-3.98 (m, 2H), 3.72-3.64 (m, 1H), 3.58-3.50(m, 3H), 2.91-2.73 (m, 3H), 2.65-2.39 (m, 2H), 2.19-2.12 (m, 1H),2.00-1.60 (m, 5H), 1.53-1.47 (m, 1H), 1.40-1.05 (m, 2H). LRMS(M+H)=375.13

Example 2[(1R,4′S)-6-methyl-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl](4-phenylpiperidin-1-yl)methanone

Step 1: 6-bromo-3,4-dihydronaphthalen-1(2H)-one

To a suspension of 6-amino-3,4-dihydro-2H-naphthalen-1-one (20.5 g, 127mmol) in 25% HBr (aq) (1017 ml) at 0° C. was added a solution of sodiumnitrite (10.53 g, 153 mmol) in water (50 ml) dropwise at a rate as tomaintain the temperature below 3°. The cooled reaction mixture was thenadded to a cooled solution of copper(I) bromide (18.79 g, 131 mmol) inHBr (98 ml, 865 mmol). When the addition was done, the reaction mixturewas stirred at 0° C. for 1 h, then warmed to rt. Water (380 mL) wasadded and the product was extracted with a mixture of Et₂O/EtOAc (8:2,3×). The organic layer was dried over Na₂SO₄, filtered, and concentratedin vacuo to give a dark brown crude oil. The crude was purified bydistillation (3 mm Hg) to give 16.415 g of6-bromo-3,4-dihydro-2H-naphthalen-1-one.

¹H NMR (CDCl₃): δ 7.89 (d, J=8.6 Hz, 1H); 7.44 (d, J=6.8 Hz, 2H); 2.94(t, J=6.1 Hz, 2H); 2.65 (t, J=6.5 Hz, 2H); 2.14 (t, J=6.4 Hz, 2H). LRMS(M+H)=226.8

Step 2: Ethyl(2E)-(6-bromo-3,4-dihydronaphthalen-1(2H)-ylidene)ethanoate

To a suspension of NaH (2.73 g, 68.4 mmol in THF (190 ml) at roomtemperature was added triethyl phosphonoacetate (31.3 ml, 157 mmol)dropwise. The resulting solution was stirred at room temperature for 1h. Then 6-bromo-3,4-dihydronaphthalen-1(2H)-one (19.5839 g, 87 mmol) wasadded in one portion and the reaction mixture stirred overnight. Thereaction mixture was quenched with 1N HCl to pH˜1. The mixture wasextracted three times with EtOAc. The combined organic layers were driedover Na₂SO₄, filtered, and concentrated in vacuo to give an orange crudeoil. The crude was purified on silica gel (8% EtOAc/hexanes) affording6.7 g of Ethyl(2E)-(6-bromo-3,4-dihydronaphthalen-1(2H)-ylidene)ethanoate.

¹H NMR (CDCl₃): δ 7.53-7.46 (m, 1H); 7.32 (d, J=6.6 Hz, 2H); 6.30 (s,1H); 4.20 (q, J=7.1 Hz, 2H); 3.19-3.12 (m, 2H); 2.77 (t, J=6.2 Hz, 2H);1.84 (p, J=6.3 Hz, 2H); 1.31 (t, J=7.1 Hz, 3H). LRMS (M+H)=296.74

Step 3: Ethyl(1R,4′S)-1′-benzyl-6-bromo-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidine]-4′-carboxylate

To a solution of N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine(6.85 ml, 26.8 mmol) and[6-Bromo-3,4-dihydro-2H-naphthalen-(E)-ylidene]-acetic acid ethyl ester(7.9 g, 26.8 mmol) in CH₂Cl₂ (14.33 ml) at 0° C. was added TFA (0.206ml, 2.68 mmol) dropwise. The ice bath was removed and the reactionmixture was stirred at room temperature. The process of the reaction wasfollowed by LC/MS. N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine(6.85 ml, 26.8 mmol) was added after every 2 h and stirred at roomtemperature till LC/MS showed no SM. The solution was diluted withCH₂Cl₂, washed three times with saturated aqueous NaHCO₃, dried,filtered, concentrated, and purified on silica gel (10% EtOAc/hexanes)affording 8.85 g of ethyl(1R,4′S)-1′-benzyl-6-bromo-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidine]-4′-carboxylate.

¹H NMR (CDCl₃): δ 7.59 (d, J=8.5 Hz, 1H); 7.33-7.22 (m, 5H); 7.22-7.15(m, 1H); 7.13 (s, 1H); 4.04 (q, J=7.1 Hz, 2H); 3.72-3.58 (m, 2H);3.33-3.23 (m, 1H); 3.17-3.07 (m, 1H); 2.98-2.88 (m, 1H); 2.86 (d, J=9.2Hz, 1H); 2.74-2.53 (m, 2H); 2.51 (d, J=9.2 Hz, 1H); 1.81-1.75 (m, 2H);1.74-1.53 (m, 2H); 1.13 (t, J=7.1 Hz, 3H). LRMS (M+H)=429.72

Step 4: 1′-tert-butyl 4′-ethyl(1R,4′S)-6-bromo-3,4-dihydro-1′H,2H-spiro[naphthalene-1,3′-pyrrolidine]-1′,4′-dicarboxylate

To a solution of ethyl(1R,4′S)-1′-benzyl-6-bromo-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidine]-4′-carboxylate(8.85 g, 20.66 mmol) at 0° C. was added 1-chloroethyl chloroformate(2.68 ml, 24.79 mmol) dropwise. The reaction mixture was stirred at 0°C. for 15 minutes, warmed to room temperature then heated to 40° C. for2 hours. The reaction was cooled to room temperature concentrated invacuo. The residue was dissolved in MeOH (275 ml) and heated to refluxfor 1 hour. The crude amine was cooled to room temperature, concentratedin vacuo, and reconstituted in THF (207 ml). Boc₂O (4.96 g, 22.73 mmol)was added to the solution followed by DIPEA (7.22 ml, 41.3 mmol). Thereaction mixture was stirred at room temperature overnight. The solutionconcentrated, dissolved in CH₂Cl₂ and washed with water. The organic wasdried, filtered, concentrated, and purified on silica gel (15%EtOAc/hexanes) affording 7.1 g of 1′-tert-butyl 4′-ethyl(1R,4′S)-6-bromo-3,4-dihydro-1′H,2H-spiro[naphthalene-1,3′-pyrrolidine]-1′,4′-dicarboxylate.

¹H NMR (CDCl₃): δ 7.31 (dd, J=8.5, 2.1 Hz, 1H); 7.26-7.18 (m, 2H);4.14-4.05 (m, 2H); 3.95 (ddd, J=15.1, 10.8, 7.1 Hz, 1H); 3.81-3.68 (m,3H); 3.61 (d, J=11.1 Hz, 1H); 3.47-3.32 (m, 2H); 2.75-2.68 (m, 2H);1.91-1.77 (m, 2H); 1.76-1.57 (m, 2H); 1.48 (d, J=12.1 Hz, 9H); 1.05 (dt,J=14.7, 7.1 Hz, 3H). LRMS (M+H)=439.74

Step 5:(1R,4′S)-6-bromo-1′-(tert-butoxycarbonyl)-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidine]-4′-carboxylicacid

To a solution of l′-tert-butyl 4′-ethyl(1R,4′S)-6-bromo-3,4-dihydro-1′H,2H-spiro[naphthalene-1,3′-pyrrolidine]-1′,4′-dicarboxylate(7.1 g, 16.20 mmol) in THF/MeOH/H2O (3:1:1, 40.5 ml) at room temperaturewas added sodium hydroxide (3M, 16.20 ml, 48.6 mmol) in one portion. Thereaction mixture was heated to 55° C. and stirred for 2 hours. Thesolution was cooled to room temperature, neutralized with 2N HCl, andconcentrated to dryness. The residue was diluted with MeOH/chloroform(1:9) and filtered to remove the salt. The filtrate was concentrated togive 6.55 g of crude(1R,4′S)-6-bromo-1′-(tert-butoxycarbonyl)-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidine]-4′-carboxylicacid. The crude was not purified.

¹H NMR (399 MHz, CD 30D): δ 7.42-7.28 (m, 3H); 3.76-3.57 (m, 5H);2.80-2.74 (m, 3H); 1.93 (s, 1H); 1.79-1.68 (m, 4H); 1.48 (d, J=13.4 Hz,9H). LRMS (M+H)=411.72

Step 6: tert-butyl(1R,4′S)-6-bromo-4′-[(4-phenylpiperidin-1-yl)carbonyl]-3,4-dihydro-1′H,2H-spiro[naphthalene-1,3′-pyrrolidine]-1′-carboxylate

To a solution of(1R,4′S)-6-bromo-1′-(tert-butoxycarbonyl)-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidine]-4′-carboxylicacid (1.5 g, 3.66 mmol), 4-phenylpiperidine (0.589 g, 3.66 mmol), andBOP (2.425 g, 5.48 mmol) in CH₂Cl₂ (73 ml) at room temperature was addedDIPEA (0.207 ml, 1.187 mmol) in one portion. The reaction mixture wasstirred for 15 hours. The solution was diluted with CH₂Cl₂, washed withwater (1×), brine (1×), dried, filtered, concentrated, and purified onsilica gel (10%-50% EtOAc/hexanes) affording 1.3 g tert-butyl(1R,4′S)-6-bromo-4′-[(4-phenylpiperidin-1-yl)carbonyl]-3,4-dihydro-1′H,2H-spiro[naphthalene-1,3′-pyrrolidine]-1′-carboxylate.

¹H NMR (CDCl₃): δ 7.31 (t, J=14.4 Hz, 5H); 7.24-7.16 (m, 1H); 7.12 (s,1H); 6.98 (d, J=7.2 Hz, 1H); 4.73 (d, J=13.1 Hz, 1H); 4.07 (d, J=10.2Hz, 1H); 3.71 (d, J=13.9 Hz, 2H); 3.67-3.51 (m, 3H); 2.73 (s, 2H); 2.52(s, 2H); 1.83 (d, J=13.6 Hz, 1H); 1.72 (s, 4H); 1.47 (d, J=7.8 Hz, 9H);1.17 (t, J=12.9 Hz, 1H). LRMS (M+H)=554.87

Step 7:[(1R,4′S)-6-methyl-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl](4-phenylpiperidin-1-yl)methanone

To a microwave tube equipped with a stir bar was added Pd(Ph₃P)₄ (94 mg,0.081 mmol) and potassium carbonate (164 mg, 1.185 mmol). The tube wasflushed with argon. Then trimethylboroxine (0.028 ml, 0.203 mmol) wasadded followed by tert-butyl(1R,4′S)-6-bromo-4′-[(4-phenylpiperidin-1-yl)carbonyl]-3,4-dihydro-1′H,2H-spiro[naphthalene-1,3′-pyrrolidine]-1′-carboxylate(100 mg, 0.181 mmol) in DMF (0.9 ml). The reaction mixture was heated to105° C. under N₂ for 15 hours. The mixture was cooled to roomtemperature, and filtered through Celite. The wet cake was washedseveral times with EtOAc. The combined organics were washed once withwater and brine, dried, filtered, concentrated. The crude was dissolvedin CH₂Cl₂ (20 ml). QuadraPure TU (1 g) was added and the mixture wasstirred at 35° C. for 16 hours. The mixture was filtered through Celiteand the wet cake was washed several times with CH₂Cl₂. The combinedorganics were concentrated and purified by reverse phase HPLC. Thedesired fractions were free based with 1N NaOH and extracted three timeswith CH₂Cl₂. The residue was dissolved in CH₂Cl₂. TFA was added and thereaction was stirred at room temperature for 1 hour. The solution wasconcentrated, basified with 1N NaOH, and extracted three times withCH₂Cl₂. The combined organics were dried, filtered, and concentrated togive the free amine.

¹H NMR (399 MHz, CDCl₃): δ 7.36 (d, J=8.1 Hz, 1H); 7.21 (t, J=7.9 Hz,3H); 7.12 (d, J=7.5 Hz, 1H); 7.04 (d, J=7.2 Hz, 2H); 6.88 (s, 1H); 4.78(t, J=15.1 Hz, 1H); 3.81 (dd, J=11.7, 5.6 Hz, 1H); 3.67-3.58 (m, 1H);3.51-3.25 (m, 2H); 3.27-3.13 (m, 1H); 3.05 (d, J=12.0 Hz, 1H); 2.76-2.68(m, 2H); 2.65-2.49 (m, 4H); 2.26 (d, J=20.3 Hz, 3H); 1.95-1.53 (m, 6H);1.43 (td, J=12.7, 4.1 Hz, 1H); 1.14 (s, 1H). LRMS (M+H)=388.90

Example 3[(4R,4′S)-8-methoxy-2,3-dihydrospiro[chromene-4,3′-pyrrolidin]-4′-yl][(2S,4R)-2-(3,3-difluorocyclohexyl)-4-phenylpiperidin-1-yl]methanone

Step 1: 1-Methoxy-2-(methoxymethoxy)benzene

To a mixture of compound 1 (50 g, 0.4 mol) in DCM (500 mL) were addedMOMCl (38.64 g, 0.48 mol) and DIEA (77.4 g, 0.6 mol) at 0° C. Themixture was stirred at room temperature overnight, diluted with EtOAc,and washed with 1N HCl solution. The organic layer were washed withbrine, dried over Na₂SO₄, filtered, and concentrated in vacuo.Purification on silica gel (PE:EA=20:1) gave 64 g of compound 2 in 99%yields.

¹H NMR CDCl₃ (400 MHz, CDCl₃): δ 7.12 (d, J=8.0 Hz, 1H), 6.95 (d, J=8.0Hz, 1H), 6.82 (t, J=8.0 Hz, 2H), 5.21 (s, 2H), 3.86 (s, 3H), 3.5 (s,3H).

Step 2: 1-Iodo-3-methoxy-2-(methoxymethoxy)benzene

To a mixture of compound 2 (48 g, 0.29 mol) in THF (600 mL) was addedn-BuLi (197 mL, 1.6 M) at −78° C. After 2 h, a solution of I₂ (40 g,0.16 mol) in THF (200 mL) was added dropwise at −50° C. The reactionmixture was stirred at room temperature overnight, quenched by NH₄Cl andNa₂S₂O₅ solutions at 0° C., and extracted with EA. The combined extractswere washed with brine, dried over Na₂SO₄ and then purified on silicagel (PE:EA=60:1) to give 64 g of compound 3 in 50% yields.

¹H NMR (400 MHz, CDCl₃): δ 7.28˜7.36 (m, 1H), 7.06˜7.12 (m, 1H),6.68˜6.76 (m, 1H), 5.16 (s, 2H), 3.82 (s, 3H), 3.46 (s, 3H).

Step 3: 2-Iodo-6-methoxyphenol

To a mixture of compound 3 (52 g, 0.18 mol) in MeOH (400 mL) was addedHCl/MeOH (100 mL, 2 M) at 0° C. The reaction mixture was stirred at RTfor 4 h, then concentrated to give 42 g of compound 4 in 95% yields.

¹H NMR (400 MHz, CDCl₃): δ 7.12 (d, J=8.0 Hz, 1H), 6.70 (d, J=8.0 Hz,1H), 6.65 (t, J=8.0 Hz, 1H), 4.46 (s, 1H), 3.75 (s, 3H).

Step 4: 3-(2-Iodo-6-methoxyphenoxy)propan-1-ol

A mixture of compound 4 (40 g, 0.16 mol), Br(CH₂)₃OH (33.3 g, 0.24 mol)and Cs₂CO₃ (104.3 g, 0.32 mol) in DMF (200 mL) was stirred at roomtemperature overnight, then diluted with water. The resulting mixturewas extracted with EA. The combined extracts were washed with brine,dried over Na₂SO₄ and then purified on silica gel (PE:EA=30:1) to give48 g of compound 5 in 60% yields.

¹H NMR (400 MHz, CDCl₃): δ 7.20˜7.23 (m, 1H), 6.75˜6.78 (m, 1H),6.68˜6.72 (m, 1H), 3.98˜4.01 (m, 2H), 3.80˜3.83 (m, 2H), 3.40˜3.44 (m,2H), 1.90˜1.93 (m, 3H).

Step 5: 3-(2-Iodo-6-methoxyphenoxy)propanal

To a solution of compound 5 (48 g, 0.16 mol) in DCM (500 mL) at 0° C.were added Py.SO₃ (50.9 g, 0.32 mol), DIEA (51.6 g, 0.4 mol) and DMSO(18.72 g, 0.24 mol). The mixture was stirred at 0° C. for 1 h and thenquenched by water, extracted with EA. The combined extracts were driedover Na₂SO₄ and filtered. The filtrate was concentrated to give 48 g ofcompound 6. It was used directly in the next step without furtherpurification.

Step 6: Ethyl (2E)-5-(2-iodo-6-methoxyphenoxy)pent-2-enoate

To a solution of ethyl 2-(diethoxyphosphoryl)acetate (62.7 g, 0.28 mol)in THF (500 mL) at 0° C. was added NaH (6.77 g, 0.28 mol). Afterstirring for 1 h, a solution of compound 6 (48 g, 0.16 mol) in THF wasadded dropwise. The mixture was stirred at room temperature overnight,quenched with water, and extracted with EA. The combined extracts weredried over Na₂SO₄ and filtered. The filtrate was concentrated andpurified on silica gel (PE:EA=30:1) to give 13 g of compound 7 in 30%yields.

¹H NMR (400 MHz, CDCl₃): δ 7.25˜7.28 (m, 1H), 7.03˜7.07 (m, 1H),6.78˜6.82 (m, 1H), 6.70˜6.75 (m, 1H), 5.9˜5.97 (m, 1H), 4.10˜4.15 (m,2H), 4.00˜4.05 (m, 2H), 3.75˜3.78 (m, 3H), 2.64˜2.70 (m, 2H), 1.53 (s,3H). LRMS (M+H⁺): 377.

Step 7: Ethyl (2E)-(8-methoxy-2,3-dihydro-4H-chromen-4-ylidene)ethanoate

A mixture of compound 7 (12 g, 0.032 mol), Ag₂CO₃ (17.6 g, 0.064 mmol),Pd(AcO)₂ (2.5 g, 0.016 mmol) and PPh₃ (8.416 g, 0.032 mmol) in toluene(200 mL) was refluxed overnight, filtered, and concentrated in vacuo.Purification on silica gel (PE:EA=30:1) gave 3 g of compound 8 in 39%yields.

¹H NMR (400 MHz, CDCl₃): δ 7.09˜7.11 (m, 1H), 6.76˜6.82 (m, 1H), 6.28(s, 1H), 4.22˜4.24 (m, 2H), 4.10˜4.13 (m, 2H), 3.81 (s, 3H), 3.33 (s,3H), 1.24˜1.26 (m, 3H). LRMS (M+H⁺): 249.

Step 8: Ethyl(1R,4′S)-8-methoxy-1′-benzyl-2,3-dihydrospiro[chromene-4,3′-pyrrolidine]-4′-carboxylate

To a mixture of compound 8 (3 g, 12 mmol) andN-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (8.5 g, 36 mmol)in DCM (5 mL) at 0° C. was added TFA (0.136 g, 1 M in DCM). The mixturewas stirred at room temperature overnight, and washed with NaHCO₃solution. The organic layer was dried over Na₂SO₄, filtered, andconcentrated in vacuo. Purification on silica gel (PE:EA=50:1 to 10:1)gave 4.5 g of compound 9 in 99% yields.

¹H (400 MHz, CDCl₃): δ 7.20˜7.22 (m, 5H), 6.86˜6.88 (m, 1H), 6.70˜6.74(m, 1H), 6.61˜6.64 (m, 1H), 4.50˜4.53 (m, 2H), 4.00˜4.03 (m, 2H), 3.84(s, 3H), 3.69 (s, 2H), 3.32 (s, 2H), 2.95 (t, J=12.0 Hz, 2H), 2.61 (d,J=8.0 Hz, 1H), 1.90 (s, 2H), 1.10˜1.14 (m, 3H).

LRMS (M+H⁺): 382

Step 9: 1′-tent-Butyl 4′-ethyl(4R,4′S)-8-methoxy-1′-benzyl-2,3-dihydrospiro[chromene-4,3′-pyrrolidine]-1′,4′-dicarboxylate

To a mixture of compound 9 (4.5 g, 11.8 mmol) in EtOH (400 mL) was addedPd/C (450 mg) and Boc₂O (10 g, 70.8 mmol). The mixture was stirred at50° C. under H₂ (50 Psi) overnight, and then filtered. The filtrate waspurified on silica gel to give 4.5 g of compound 10 in 95% yields.

¹H (400 MHz, CDCl₃): δ 6.86 (d, J=8.0 Hz, 2H), 6.74 (d, J=8.0 Hz, 1H),4.10˜4.14 (m, 2H), 3.90˜4.93 (m, 2H), 3.85 (s, 3H), 3.6˜3.64 (m, 2H),3.4˜3.5 (m, 2H), 2.82˜2.85 (m, 1 H), 1.80˜1.85 (m, 2H), 1.43 (s, 9H),1.00˜1.03 (m, 3H). LRMS (M+H⁺): 391

Step 10:(1R,4′S)-8-Methoxy-1′-(tert-butoxycarbonyl)-2,3-dihydrospiro[chromene-4,3′-pyrrolidine]-4′-carboxylicacid

A mixture of compound 10 (1 g, 2.56 mmol) in NaOH/MeOH (20 mL, 2 M) wasstirred at room temperature for 3 h. The mixture was acidified to pH 2˜3with 2M HCl and extracted to times with CH₂Cl₂. The combined organiclayers were dried over Na₂SO₄ and concentrated to give 0.85 g ofcompound 11 in 91% yields.

LRMS (M+H⁺): 364.

Step 11:[(4R,4′S)-8-methoxy-1′-(tert-butoxycarbonyl)-2,3-dihydrospiro[chromene-4,3′-pyrrolidin]-4′-yl][(2S,4R)-2-(3,3-difluorocyclohexyl)-4-phenylpiperidin-1-yl]methanone

A solution of compound 11 (100 mg, 0.275 mmol),(2S,4R)-2-(3,3-difluorocyclohexyl)-4-phenylpiperidine (77 mg, 0.275mmol), HATU (171 mg, 0.45 mmol) and DIEA (71 mg, 0.6 mmol) in DMF werestirred at room temperature overnight, diluted with EA, and washed withwater. The organic layer was dried over Na₂SO₄, filtered, andconcentrated in vacuo. Purification on silica gel gave 70 mg of compound12 in 41% yields.

LRMS (M+H⁺): 625.

Step 12:[(4R,4′S)-8-methoxy-2,3-dihydrospiro[chromene-4,3′-pyrrolidin]-4′-yl][(2S,4R)-2-(3,3-difluorocyclohexyl)-4-phenylpiperidin-1-yl]methanone

To a solution of compound 12 (70 mg) in 2 mL of MeOH was added asolution of HCl/MeOH (2 mL, 2 M). After 2 h at room temperature, themixture was concentrated in vacuo to give[(4R,4′S)-8-methoxy-2,3-dihydrospiro[chromene-4,3′-pyrrolidin]-4′-yl][(2S,4R)-2-(3,3-difluorocyclohexyl)-4-phenylpiperidin-1-yl]methanoneas HCl salts.

¹H NMR (400 MHz, methanol-d₄) δ 7.08 (d, J=7.6 Hz, 1H, Ar—H), 6.99 (t,J=7.2 Hz, 2H, Ar—H), 6.89 (d, J=7.2 Hz, 1H, Ar—H), 6.76 (d, J=7.2 Hz,1H, Ar—H), 6.74 (m, 1H, Ar—H), 6.73 (d, J=8.0 Hz, 1H, Ar—H), 4.08 (m,3H, CH), 3.77 (m, 2H, CH), 3.58 (m, 2H, CH), 3.45 (s, 3H, OCH₃), 3.26(m, 2H, CH), 2.93 (m, 1H, CH), 2.25 (m, 1H, CH), 1.89 (m, 2H, CH), 1.77(m, 4H, CH), 1.60 (m, 1H, CH), 1.52 (m, 1H, CH), 1.44 (m, 4H, CH), 1.31(m, 1H, CH), 0.91 (m, 3H, CH), 0.10 (m, 1H, CH). LRMS (M+H⁺): 525.

Examples 4-137

The following compounds were prepared similar to Examples 1 and 2 usingthe starting materials and methods described herein, and applying theknowledge of one of skilled in the art.

TABLE 2 Parent Ex Scheme Product Name MW 4 1

(1R,4′S)-2,3- dihydrospiro[indene- 1,3′-pyrrolidin]-4′-yl(4-phenylpiperidin-1- yl)methanone 360.504 5 1

(1R,4′S)-2,3- dihydrospiro[indene- 1,3′-pyrrolidin]-4′-yl[(2S,4R)-4-phenyl-2- (propan-2-yl)piperidin- 1-yl]methanone 402.585 61

(1R,4′S)-3,4-dihydro- 2H-spiro[naphthalene- 1,3′-pyrrolidin]-4′-yl(4-phenylpiperidin-1- yl)methanone 374.531 7 1

(1R,4′S)-3,4-dihydro- 2H-spiro[naphthalene- 1,3′-pyrrolidin]-4′-yl[(2S,4R)-4-phenyl-2- (propan-2-yl)piperidin- 1-yl]methanone 416.612 81

(4R,4′S)-2,3- dihydrospiro[chromene- 4,3′-pyrrolidin]-4′-yl(4-phenylpiperidin-1- yl)methanone 376.503 9 1

(1R,4′S)-3,4-dihydro- 2H-spiro[naphthalene- 1,3′-pyrrolidin]-4′-yl[(2S,4R)-2,4- diphenylpiperidin-1- yl]methanone 450.629 10 1

(1S,4′S)-3,4-dihydro- 2H-spiro[naphthalene- 1,3′-pyrrolidin]-4′-yl[2-(2-methoxypropan-2- yl)piperidin-1-yl] methanone 370.54 11 1

[(1R,4′S)-4,4-dimethyl- 3,4-dihydro-2H-spiro [naphthalene-1,3′-pyrrolidin]-4′-yl](4- phenylpiperidin-1-yl) methanone 402.585 12 1

[(2S,4R)-2-cyclohexyl- 4-phenylpiperidin-1- yl][(1R,4′S)-3,4-dihydro-2H-spiro [naphthalene-1,3′- pyrrolidin]-4′-yl] methanone 456.67713 1

[(2R,4S)-2-cyclohexyl- 4-phenylpiperidin-1- yl][(1R,4′S)-3,4-dihydro-2H- spiro[naphthalene-1,3′- pyrrolidin]-4′-yl] methanone 456.67714 2

[(1R,4′S)-7-bromo-3,4- dihydro-2H-spiro [naphthalene-1,3′-pyrrolidin]-4′-yl](4- phenylpiperidin-1-yl) methanone 453.427 15 1

(1S,4′S)-3,4-dihydro- 2H-spiro[naphthalene- 1,3′-pyrrolidin]-4′-yl[2-(3-methoxypentan-3- yl)piperidin-1-yl] methanone 398.594 16 1

[(2S,4R)-2-cyclohexyl- 4-phenylpiperidin-1- yl][(1R,4′S)-2,3-dihydrospiro[indene- 1,3′-pyrrolidin]-4′-yl] methanone 442.65 17 2

[(1R,4′S)-6-bromo-3,4- dihydro-2H-spiro [naphthalene-1,3′-pyrrolidin]-4′-yl](4- phenylpiperidin-1- yl)methanone 453.427 18 1

[(1R,4′S)-6-methoxy- 3,4-dihydro-2H-spiro [naphthalene-1,3′-pyrrolidin]-4′-yl](4- phenylpiperidin-1-yl) methanone 404.557 19 2

[(1R,4′S)-6-chloro-3,4- dihydro-2H-spiro [naphthalene-1,3′-pyrrolidin]-4′-yl](4- phenylpiperidin-1-yl) methanone 408.976 20 2

[(1R,4′S)-6-bromo-3,4- dihydro-2H-spiro [naphthalene-1,3′-pyrrolidin]-4′-yl](1′H- spiro[indene-1,4'- piperidin]-1′-yl) methanone477.449 21 1

(1R,4′S)-2,3- dihydrospiro[indene- 1,3′-pyrrolidin]-4′- yl[(2S,4R)-2,4-diphenylpiperidin-1-yl] methanone 436.602 22 2

[(1R,4′S)-6-bromo-3,4- dihydro-2H-spiro [naphthalene-1,3′-pyrrolidin]-4′- yl][(2S,4R)-2,4- diphenylpiperidin-1-yl] methanone529.525 23 1

(1S,4′S)-3,4-dihydro- 2H-spiro[naphthalene- 1,3′-pyrrolidin]-4′-yl(4-phenylpiperidin-1-yl) methanone 374.531 24 1

(3R,4S)-2′,3′-dihydro- 1′H-spiro[pyrrolidine- 3,4'-quinolin]-4-yl(4-phenylpiperidin-1-yl) methanone 375.518 25 2

[(1R,4′S)-6-bromo-3,4- dihydro-2H-spiro [naphthalene-1,3′-pyrrolidin]-4′-yl] [(2S,4R)-4-phenyl-2- (propan-2-yl)piperidin-1-yl]methanone 495.508 26 1

[(1R,4′S)-6-hydroxy- 3,4-dihydro-2H-spiro [naphthalene-1,3′-pyrrolidin]-4′-yl](4- phenylpiperidin-1-yl) methanone 390.53 27 2

[(1R,4′S)-5-bromo-3,4- dihydro-2H-spiro [naphthalene-1,3′-pyrrolidin]-4′-yl](4- phenylpiperidin-1-yl) methanone 453.427 28 1

[(1R,4′S)-6-fluoro-3,4- dihydro-2H-spiro [naphthalene-1,3′-pyrrolidin]-4′-yl](4- phenylpiperidin-1-yl) methanone 392.521 29 1

(3R,4S)-7′,8′-dihydro- 6′H-spiro[pyrrolidine- 3,5′-quinolin]-4-yl(4-phenylpiperidin-1-yl) methanone 375.518 30 2

[(1R,4′S)-5-bromo-2,3- dihydrospiro[indene- 1,3′-pyrrolidin]-4′-yl](4-phenylpiperidin-1-yl) methanone 439.4 31 2

(4-phenylpiperidin-1- yl)[(1R,4′S)-5-(propan- 2-yl)-3,4-dihydro-2H-spiro[naphthalene-1,3′- pyrrolidin]-4′-yl] methanone 416.612 32 2

[(1R,4′S)-6-bromo-3,4- dihydro-2H-spiro [naphthalene-1,3′-pyrrolidin]-4′-yl] [(2S,4R)-2-cyclohexyl- 4-phenylpiperidin-1-yl]methanone 535.573 33 2

[(1R,4′S)-6-bromo-3,4- dihydro-2H-spiro [naphthalene-1,3′-pyrrolidin]-4′-yl] [(2R,4S)-2-cyclohexyl- 4-phenylpiperidin-1-yl]methanone 535.573 34 1

[(3R,4S)-1′- (methylsulfonyl)-2′,3′- dihydro-1′H-spiro[pyrrolidine-3,4′- quinolin]-4-yl](4- phenylpiperidin-1-yl) methanone453.608 35 2

[(3R,4S)-2′-chloro-7′,8′- dihydro-6′H-spiro [pyrrolidine-3,5′-quinolin]-4-yl](4- phenylpiperidin-1-yl) methanone 409.963 36 2

[(3R,4S)-2′-chloro-7′,8′- dihydro-6′H-spiro [pyrrolidine-3,5′-quinolin]-4-yl][(2S,4R)- 4-phenyl-2-(propan-2- yl)piperidin-1-yl]methanone 452.045 37 2

[(3R,4S)-2′-bromo-7′,8′- dihydro-6′H-spiro [pyrrolidine-3,5′-quinolin]-4-yl](4- phenylpiperidin-1-yl) methanone 454.414 38 1

(3R,4S)-2′,3′- dihydrospiro[pyrrolidine- 3,4′-thiochromen]-4-yl(4-phenylpiperidin-1- yl)methanone 392.568 39 2

[(3R,4S)-2′- (dimethylamino)-7′,8′- dihydro-6′H-spiro [pyrrolidine-3,5′-quinolin]-4-yl](4- phenylpiperidin-1-yl) methanone 418.587 40 2

[(3R,4S)-2′- (methylamino)-7′,8′- dihydro-6′H-spiro [pyrrolidine-3,5′-quinolin]-4-yl](4- phenylpiperidin-1-yl) methanone 404.56 41 2

[(1R,4′S)-6-ethenyl-3,4- dihydro-2H-spiro [naphthalene-1,3′-pyrrolidin]-4′-yl](4- phenylpiperidin-1-yl) methanone 400.569 42 2

[(1R,4′S)-5-amino-2,3- dihydrospiro[indene- 1,3′-pyrrolidin]-4′-yl](4-phenylpiperidin-1-yl) methanone 375.518 43 2

[(1R,4′S)-5- (dimethylamino)-2,3- dihydrospiro[indene-1,3′-pyrrolidin]-4′-yl](4- phenylpiperidin-1-yl) methanone 403.572 44 2

[(1R,4′S)-6-ethyl-3,4- dihydro-2H-spiro [naphthalene-1,3′-pyrrolidin]-4′-yl](4- phenylpiperidin-1-yl) methanone 402.585 45 1

(4S,4′S)-2,3-dihydro- 1H-spiro[isoquinoline- 4,3′-pyrrolidin]-4′-yl(4-phenylpiperidin-1-yl) methanone 375.518 46 2

[(3R,4S)-2′-chloro-7′,8′- dihydro-6′H-spiro [pyrrolidine-3,5′-quinolin]-4-yl](4- phenylpiperidin-1-yl) methanone 409.963 47 1

[(3R,4S)-1′,1′-dioxido- 2′,3′-dihydrospiro [pyrrolidine-3,4′-thiochromen]-4-yl](4- phenylpiperidin-1-yl) methanone 424.566 48 2

[(1R,4′S)-6-methyl-3,4- dihydro-2H-spiro [naphthalene-1,3′-pyrrolidin]-4′-yl](4- phenylpiperidin-1-yl) methanone 388.558 49 2

(4-phenylpiperidin-1- yl)[(1R,4′S)-6-(propan- 2-yl)-3,4-dihydro-2H-spiro[naphthalene-1,3′- pyrrolidin]-4′-yl] methanone 416.612 50 2

[(3R,4S)-2′-methyl- 7′,8′-dihydro-6′H- spiro[pyrrolidine-3,5′-quinolin]-4-yl](4- phenylpiperidin-1-yl) methanone 389.545 51 2

[(3R,4S)-2′-chloro-7′,8′- dihydro-6′H-spiro [pyrrolidine-3,5′-quinolin]-4-yl] [(2R,4S)-2-cyclohexyl- 4-phenylpiperidin-1-yl] methanone492.11 52 2

[(3R,4S)-2′-chloro-7′,8′- dihydro-6′H-spiro [pyrrolidine-3,5′-quinolin]-4-yl] [(2S,4R)-2-cyclohexyl- 4-phenylpiperidin-1-yl] methanone492.11 53 2

[(3R,4S)-2′-chloro-7′,8′- dihydro-6′H-spiro [pyrrolidine-3,5′-quinolin]-4-yl] [(2R,4R)-2-cyclohexyl- 4-phenylpiperidin-1-yl] methanone492.11 54 2

[(3R,4S)-2′-chloro-7′,8′- dihydro-6′H-spiro [pyrrolidine-3,5′-quinolin]-4-yl][(2S,4S)- 2-cyclohexyl-4- phenylpiperidin-1-yl] methanone492.11 55 2

[(1R,4′S)-6-(morpholin- 4-yl)-3,4-dihydro-2H- spiro[naphthalene-1,3′-pyrrolidin]-4′-yl](4- phenylpiperidin-1-yl) methanone 459.637 56 2

[(1R,4′S)-6-tert-butyl- 3,4-dihydro-2H-spiro [naphthalene-1,3′-pyrrolidin]-4′-yl](4- phenylpiperidin-1- yl)methanone 430.639 57 2

[(2S,4R)-2-cyclohexyl- 4-phenylpiperidin-1-yl] [(3R,4S)-7′,8′-dihydro-6′H-spiro[pyrrolidine- 3,5′-quinolin]-4-yl] methanone 457.665 58 2

[(1R,4′S)-6- cyclopropyl-3,4- dihydro-2H-spiro [naphthalene-1,3′-pyrrolidin]-4′-yl](4- phenylpiperidin-1- yl)methanone 414.596 59 2

(4-phenylpiperidin-1- yl)[(1R,4′S)-6- (trifluoromethyl)-3,4-dihydro-2H-spiro [naphthalene-1,3′- pyrrolidin]-4′-yl] methanone 442.52960 2

[(3R,4S)-2′-chloro-7′,8′- dihydro-6′H-spiro [pyrrolidine-3,5′-quinolin]-4-yl] [(2S,4R)-2,4- diphenylpiperidin-1- yl]methanone 486.06261 2

[(2S,4R)-2,4- diphenylpiperidin-1- yl][(3R,4S)-2′-methyl-7′,8′-dihydro-6′H-spiro [pyrrolidine-3,5′- quinolin]-4-yl] methanone465.644 62 2

[(3R,4S)-2′-bromo-7′,8′- dihydro-6′H-spiro [pyrrolidine-3,5′-quinolin]-4-yl] [(2S,4R)-2-cyclohexyl- 4-phenylpiperidin-1-yl] methanone536.561 63 2

[(2S,4R)-2-cyclohexyl- 4-phenylpiperidin-1- yl][(3R,4S)-2′-methyl-7′,8′-dihydro-6′H-spiro [pyrrolidine-3,5′- quinolin]-4-yl] methanone471.692 64 2

[(1R,4′S)-6- (difluoromethyl)-3,4- dihydro-2H-spiro [naphthalene-1,3′-pyrrolidin]-4′-yl](4- phenylpiperidin-1-yl) methanone 424.539 65 2

[(1R,4′S)-6- (hydroxymethyl)-3,4- dihydro-2H-spiro [naphthalene-1,3′-pyrrolidin]-4′-yl](4- phenylpiperidin-1-yl) methanone 404.557 66 2

[(1R,4′S)-6- (aminomethyl)-3,4- dihydro-2H-spiro [naphthalene-1,3′-pyrrolidin]-4′-yl](4- phenylpiperidin-1-yl) methanone 403.572 67 2

[(1R,4′S)-6- (fluoromethyl)-3,4- dihydro-2H-spiro [naphthalene-1,3′-pyrrolidin]-4′-yl](4- phenylpiperidin-1-yl) methanone 406.548 68 1

[(2S,4R)-2-cyclohexyl- 4-phenylpiperidin-1- yl][(4S,4′S)-2,3-dihydro-1H-spiro [isoquinoline-4,3′- pyrrolidin]-4′-yl] methanone457.665 69 1

[(2S,4R)-2-cyclohexyl- 4-phenylpiperidin-1- yl][(4R,4′R)-2,3-dihydro-1H-spiro [isoquinoline-4,3′- pyrrolidin]-4′-yl] methanone457.665 70 2

[(2S,4R)-2-cyclohexyl- 4-phenylpiperidin-1-yl] [(3R,4S)-2′-(propan-2-yl)-7′,8′-dihydro-6′H- spiro[pyrrolidine-3,5′- quinolin]-4-yl] methanone499.746 71 2

(4-phenylpiperidin-1- yl)[(1R,4′S)-6-(2,2,2- trifluoro-1-hydroxyethyl)-3,4- dihydro-2H-spiro [naphthalene-1,3′-pyrrolidin]-4′-yl] methanone 472.556 72 2

[(3R,4S)-2′-methyl- 7′,8′-dihydro-6′H- spiro[pyrrolidine-3,5′-quinolin]-4-yl] [(2S,4R)-4-phenyl-2- (propan-2-yl)piperidin-1-yl]methanone 431.627 73 2

[(2S,4R)-2-cyclohexyl- 4-phenylpiperidin-1- yl][(3R,4S)-1′-oxido-7′,8′-dihydro-6′H-spiro [pyrrolidine-3,5′- quinolin]-4-yl] methanone473.664 74 2

[(2S,4R)-2-tert-butyl-4- phenylpiperidin-1-yl] [(3R,4S)-2′-methyl-7′,8′-dihydro-6′H-spiro [pyrrolidine-3,5′- quinolin]-4-yl] methanone445.654 75 1

(4-phenylpiperidin-1-yl) [(4S,4′S)-1H- spiro[isochromene-4,3′-pyrrolidin]-4′-yl] methanone 376.503 76 2

[(3R,4S)-2′-chloro-7′,8′- dihydro-6′H-spiro [pyrrolidine-3,5′-quinolin]-4-yl] [(2S,4R)-2-(pentan-3- yl)-4-phenylpiperidin-1-yl]methanone 480.099 77 2

[(3R,4S)-2′-chloro-7′,8′- dihydro-6′H-spiro [pyrrolidine-3,5′-quinolin]-4-yl](2′- phenyl-1′H-spiro [indene-1,4′-piperidin]-1′-yl)methanone 510.084 78 2

[(3R,4S)-2′-methyl- 7′,8′-dihydro-6′H- spiro[pyrrolidine-3,5′-quinolin]-4-yl] [(2S,4R)-2-(pentan-3- yl)-4-phenylpiperidin-1-yl]methanone 459.681 79 2

[(2S,4R)-2-cyclohexyl- 4-phenylpiperidin-1-yl] [(1R,4′S)-6-(hydroxymethyl)-3,4- dihydro-2H-spiro [naphthalene-1,3′-pyrrolidin]-4′-yl] methanone 486.704 80 2

[(4S)-2′-chloro-7′,8′- dihydro-6'H-spiro [pyrrolidine-3,5′-quinolin]-4-yl](4- phenyl-2- propylpiperidin-1-yl) methanone 453.052 812

[(4S)-2′-chloro-7′,8′- dihydro-6′H-spiro [pyrrolidine-3,5′-quinolin]-4-yl][2-(2- methylpropyl)-4- phenylpiperidin-1-yl] methanone466.072 82 2

[(4S)-2′-chloro-7′,8′- dihydro-6′H-spiro [pyrrolidine-3,5′-quinolin]-4-yl](4- phenyl-2- propylpiperidin-1- yl)methanone 466.072 832

[(4S)-2′-chloro-7′,8′- dihydro-6′H-spiro [pyrrolidine-3,5′-quinolin]-4-yl][2-(4- fluorophenyl)-4- phenylpiperidin-1-yl] methanone504.052 84 1

2,3-dihydrospiro [chromene-4,3′- pyrrolidin]-4′-yl(2,4-diphenylpiperidin-1-yl) methanone 452.602 85 2

(6-bromo-2,3- dihydrospiro[indene- 1,3′-pyrrolidin]-4′-yl)[2-(4-fluorophenyl)-4- phenylpiperidin-1-yl] methanone 533.489 86 2

[(3R,4S)-2′-chloro-7′,8′- dihydro-6′H-spiro [pyrrolidine-3,5′-quinolin]-4-yl](4- phenyl-2-propylazepan- 1-yl)methanone 466.072 87 2

(6-bromo-2,3- dihydrospiro[indene- 1,3′-pyrrolidin]-4′- yl)(2,4-diphenylpiperidin-1-yl) methanone 515.498 88 2

(2′-chloro-7′,8′-dihydro- 6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl)(2,4- diphenylpiperidin-1-yl) methanone 486.062 89 1

2,3-dihydrospiro [chromene-4,3′- pyrrolidin]-4′-yl[4-phenyl-2-(prop-2-en-1- yl)piperidin-1-yl] methanone 416.568 90 1

2,3-dihydrospiro [chromene-4,3′- pyrrolidin]-4′-yl[2-(2-fluorophenyl)-4- phenylpiperidin-1-yl] methanone 470.592 91 1

2,3-dihydrospiro [chromene-4,3′- pyrrolidin]-4′-yl[2-(4-fluorophenyl)-4- phenylpiperidin-1-yl] methanone 470.592 92 2

(2,4-diphenylpiperidin- 1-yl)(6-ethyl-2,3- dihydrospiro[indene-1,3′-pyrrolidin]-4′-yl) methanone 464.657 93 2

(3-benzylpiperidin-1- yl)[(3R,4S)-2′-chloro- 7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′- quinolin]-4-yl] methanone 423.99 94 2

[(3R,4S)-2′-chloro-7′,8′- dihydro-6′H-spiro [pyrrolidine-3,5′-quinolin]-4-yl](1′H- spiro[1-benzofuran-3,4′- piperidin-1′-yl) methanone437.974 95 2

[(3R,4S)-2′-chloro-7′,8′- dihydro-6′H-spiro [pyrrolidine-3,5′-quinolin]-4-yl](1,2- dihydro-1′H-spiro [indole-3,4′-piperidin]-1′-yl)methanone 436.989 96 1

(2-butyl-2,3- dihydrospiro[chromene- 4,3′-pyrrolidin]-4′- yl)(2,4-diphenylpiperidin-1- yl)methanone 508.71 97 2

(2′-chloro-7′,8′-dihydro- 6′H-spiro[pyrrolidine- 3,5′-quinolin]-4-yl)(5-phenyl-2-propylazepan- 1-yl)methanone 466.072 98 2

(2′-chloro-7′,8′-dihydro- 6′H-spiro[pyrrolidine- 3,5′-quinolin]-4-yl)[4-phenyl-2-(prop-2-en-1- yl)piperidin-1-yl] methanone 450.029 99 2

(2′-chloro-7′,8′-dihydro- 6′H-spiro[pyrrolidine- 3,5′-quinolin]-4-yl)[2-(2-fluorophenyl)-4- phenylpiperidin-1-yl] methanone 504.052 100 2

[(3R,4S)-2′-chloro-7′,8′- dihydro-6′H-spiro [pyrrolidine-3,5′-quinolin]-4-yl][2-(3- methylphenyl)-4- phenylpiperidin-1-yl] methanone500.089 101 1

(4R,4′S)-2,3- dihydrospiro[chromene- 4,3′-pyrrolidin]-4′-yl[(2S,4R)-2,4- diphenylpiperidin-1-yl] methanone 452.602 102 1

[(2S,4R)-2,4- diphenylpiperidin-1- yl][(4R,4′S)-2-methyl-2,3-dihydrospiro [chromene-4,3′- pyrrolidin]-4′-yl] methanone 466.629103 1

[(4R,4′S)-2-butyl-2,3- dihydrospiro[chromene- 4,3′-pyrrolidin]-4′-yl][(2S,4R)-2,4- diphenylpiperidin-1-yl] methanone 508.71 104 2

[(4R,4′S)-6-chloro-2,3- dihydrospiro[chromene- 4,3′-pyrrolidin]-4′-yl][(2S,4R)-2,4- diphenylpiperidin-1-yl] methanone 487.047 105 2

[(4R,4′S)-6-chloro-7- methyl-2,3- dihydrospiro[chromene-4,3′-pyrrolidin]-4′-yl] [(2S,4R)-2,4- diphenylpiperidin-1-yl] methanone501.074 106 2

[(3R,4S)-2′-chloro-1′- oxido-7′,8′-dihydro-6′H- spiro[pyrrolidine-3,5′-quinolin]-4-yl] [(2R,4S)-2,4- diphenylpiperidin-1-yl] methanone 502.061107 2

[(2R,4S)-2,4- diphenylpiperidin-1- yl][(3R,4S)-2′-ethyl-7′,8′-dihydro-6′H- spiro[pyrrolidine-3,5′- quinolin]-4-yl] methanone479.671 108 2

[(3R,4S)-2′-chloro-7′,8′- dihydro-6′H-spiro [pyrrolidine-3,5′-quinolin]-4-yl][2′-(4- fluorophenyl)-1′H- spiro[indene-1,4′-piperidin]-1′-yl] methanone 528.075 109 2

[(3R,4S)-2′-chloro-7′,8′- dihydro-6′H-spiro [pyrrolidine-3,5′-quinolin]-4-yl](2′- phenyl-1′H-spiro [indene-1,4′-piperidin]-1′-yl)methanone 510.084 110 1

(4R,4′S)-4′-{[(2S,4R)- 2,4-diphenylpiperidin-1- yl]carbonyl}-1,5,6,7-tetrahydrospiro[indole- 4,3′-pyrrolidine] 439.59 111 1

(4R,4′S)-4′-{[(2S,4R)- 2,4-diphenylpiperidin-1- yl]carbonyl}-6,7-dihydro-5H-spiro[1- benzothiophene-4,3′- pyrrolidine] 456.64 112 1

(4R,4′S)-4′-{[(2S,4R)- 2,4-diphenylpiperidin-1- yl]carbonyl}-6,7-dihydro-5H-spiro[1- benzofuran-4,3′- pyrrolidine] 440.58 113 1

(4′S,7S)-4′-{[(2S,4R)- 2,4-diphenylpiperidin-1- yl]carbonyl}-2-methyl-5,6-dihydro-4H- spiro[1,3-benzothiazole- 7,3′-pyrrolidine] 471.66 114 1

(4′S,7S)-4′-{[(2S,4R)- 2,4-diphenylpiperidin-1- yl]carbonyl}-5,6-dihydro-4H-spiro[1- benzothiophene-7,3′- pyrrolidine] 456.64 115 1

(4′S,7S)-4′-{[(2S,4R)- 2,4-diphenylpiperidin-1- yl]carbonyl}-5,6-dihydro-4H-spiro[1- benzofuran-7,3′- pyrrolidine] 440.58 116 1

(3R,4S)-4-{[(2S,4R)- 2,4-diphenylpiperidin-1- yl]carbonyl}-7′-methyl-2′,3′- dihydrospiro[pyrrolidine- 3,4′-thiopyrano[2,3-b] pyridine] 483.67117 2

(3S,4S)-2′-chloro-4- {[(2S,4R)-2,4- diphenylpiperidin-1-yl]carbonyl}-6′,7′- dihydro-5′H-spiro [pyrrolidine-3,8′- quinoline]486.05 118 2

(3R,4S)-3′-chloro-4- {[(2S,4R)-2,4- diphenylpiperidin-1-yl]carbonyl}-7′,8′- dihydro-6′H-spiro [pyrrolidine-3,5′- quinoline]486.05 119 1

(3S,4S)-4-{[(2S,4R)- 2,4-diphenylpiperidin-1- yl]carbonyl}-2′-phenyl-6′,7′-dihydro-5′H- spiro[pyrrolidine-3,8′- quinoline] 527.7 120 1

(3R,4S)-4-{[(2S,4R)- 2,4-diphenylpiperidin-1- yl]carbonyl}-3′-methyl-7′,8′-dihydro-6′H- spiro[pyrrolidine-3,5′- quinoline] 464.64 121 1

(3R,4S)-4-{[(2S,4R)- 2,4-diphenylpiperidin-1- yl]carbonyl}-4′-methyl-7′,8′-dihydro-6′H- spiro[pyrrolidine-3,5′- quinoline] 464.64 122 1

(3S,4S)-4-{[(2S,4R)- 2,4-diphenylpiperidin-1- yl]carbonyl}-3′-methyl-6′,7′-dihydro-5′H- spiro[pyrrolidine-3,8′- quinoline] 464.64 123 1

(3R,4S)-4-{[(2S,4R)- 2,4-diphenylpiperidin-1- yl]carbonyl}-2′-methyl-7′,8′-dihydro-6′H- spiro[pyrrolidine-3,5′- quinazoline] 465.63 124 1

(3R,4S)-4-{[(2S,4R)- 2,4-diphenylpiperidin-1- yl]carbonyl}-2′-phenyl-7′,8′-dihydro-6′H- spiro[pyrrolidine-3,5′- quinazoline] 527.7 125 1

(3S,4S)-4-{[(2S,4R)- 2,4-diphenylpiperidin-1- yl]carbonyl}-7′,8′-dihydro-6′H-spiro [pyrrolidine-3,5′- quinoxaline] 451.6 126 1

(3R,4S)-4-{[(2S,4R)- 2,4-diphenylpiperidin-1- yl]carbonyl}-4′-(trifluoromethyl)-7′,8′- dihydro-6′H-spiro [pyrrolidine-3,5′- quinoline]518.61 127 1

(4′S,8R)-4′-{[(2S,4R)- 2,4-diphenylpiperidin-1- yl]carbonyl}-1,3-dimethyl-6,7-dihydro- 5H-spiro[isoquinoline- 8,3′-pyrrolidine] 478.67128 1

(1R,4′S)-4′-{[(2S,4R)- 2,4-diphenylpiperidin-1- yl]carbonyl}-6,8-dimethyl-3,4-dihydro- 2H-spiro[naphthalene- 1,3′-pyrrolidine] 478.67 1291

(1R,4′S)-4′-{[(2S,4R)- 2,4-diphenylpiperidin-1- yl]carbonyl}-3,4,5,6,7,8-hexahydro- 2H-spiro[acridine-1,3′- pyrrolidine] 504.7 130 1

(4′S,9R)-4′-{[(2S,4R)- 2,4-diphenylpiperidin-1- yl]carbonyl}-1,2,3,6,7,8- hexahydrospiro[cyclope nta[c]quinoline-9,3′- pyrrolidine]520.75 131 1

(4R,4′S)-4′-{[(2S,4R)- 2,4-diphenylpiperidin-1- yl]carbonyl}-2,2-dimethyl-2,3- dihydrospiro[chromene- 4,3′-pyrrolidine] 479.65 132 2

(4R,4′S)-7-bromo-4′- {[(2S,4R)-2,4- diphenylpiperidin-1-yl]carbonyl}-2,3- dihydrospiro[chromene- 4,3′-pyrrolidine] 530.5 133 2

(3S,4′S)-6-bromo-4′- {[(2S,4R)-2,4- diphenylpiperidin-1-yl]carbonyl}spiro[1- benzofuran-3,3′- pyrrolidine] 516.47 134 2

(1R,4′S)-5-bromo-4′- {[(2S,4R)-2,4- diphenylpiperidin-1-yl]carbonyl}-2,3- dihydrospiro[indene- 1,3′-pyrrolidine] 514.5 135 1

(1S,4′S)-7-bromo-4′- {[(2S,4R)-2,4- diphenylpiperidin-1-yl]carbonyl}-4,5- dihydrospiro[3- benzoxepine-1,3′- pyrrolidine] 465.63

Compounds in Table 2 having a basic group or acidic group are depictedand named as the free base acid. Depending on the reaction andpurification conditions, various compounds in Table 1 having a basicgroup were isolated in either the free base form, or as a salt (such asHCl salt), or in both free base and salt forms.

The following compounds were prepared similar to Examples 1 to 3 usingthe starting materials and methods described herein, and applying theknowledge of one of skilled in the art.

TABLE 3 Ex. Parent No. Scheme Structure MW 136 2

462.594 137 2

532.68 138 2

534.696 139 2

478.705 140 2

522.685 141 2

470.564 142 2

448.611 143 2

556.674 144 2

487.57 145 2

514.686 146 2

524.657 147 2

556.553 148 2

498.715 149 2

537.546 150 2

507.673 151 2

484.668 152 2

486.704 153 2

471.677 154 2

496.699 155 2

478.554 156 2

555.569 157 2

506.666 158 2

576.646 159 2

488.555 160 2

472.558 161 2

471.571 162 2

476.649 163 2

514.714 164 2

537.546 165 2

533.736 166 2

525.663 167 2

501.554 168 2

452.574 169 2

462.638 170 2

489.664 171 2

573.68 172 2

502.66 173 2

537.656 174 2

522.685 175 2

524.657 176 2

476.665 177 2

542.647 178 2

445.595 179 2

488.592 180 2

473.708 181 2

498.715 182 2

491.655 183 2

524.657 184 2

488.676 185 2

502.703 186 2

450.583 187 2

446.595 188 2

610.646 189 2

474.693 190 2

592.655 191 2

544.663 192 2

570.673 193 2

488.555 194 2

501.675 195 2

420.557 196 2

542.647 197 2

420.557 198 2

507.673 199 2

532.677 200 2

525.663 201 2

507.673 202 2

434.584 203 2

522.685 204 2

476.665 205 2

521.149 206 2

556.674 207 2

591.671 208 2

543.679 209 2

542.74 210 2

505.682 211 2

526.651 212 2

508.66 213 2

560.731 214 2

509.763 215 2

497.752 216 2

481.709 217 2

545.709 218 2

559.736 219 2

471.692 220 2

500.734 221 2

397.481 222 2

413.543 223 2

412.493 224 2

466.072 225 2

536.561 226 2

465.644 227 2

479.671 228 2

524.55 229 2

459.681 230 2

406.529 231 2

609.661 232 2

525.663 233 2

507.673 234 2

501.675 235 2

431.539 236 2

524.657 237 2

446.595 238 2

448.611 239 2

471.692 240 2

464.056 241 2

452.045 242 2

473.664 243 2

486.583 244 2

450.029 245 2

488.676 246 2

555.69 247 2

503.709 248 2

510.1 249 2

510.1 250 2

494.748 251 2

506.71 252 2

482.628 253 2

466.629 254 2

488.676 255 2

553.773 256 2

539.746 257 2

545.149 258 2

565.784 259 2

551.757 260 2

530.513 261 2

480.656 262 2

476.665 264 2

452.602 265 2

502.703 266 2

503.709 267 2

485.719 268 2

459.681 269 2

459.681 270 2

501.718 271 2

522.136 272 2

512.701 273 2

502.703 274 2

541.663 275 2

493.097 276 2

498.089 277 2

481.086 278 2

518.721 279 2

502.706 280 2

514.714 281 2

555.69 282 2

555.69 283 2

471.692 284 2

566.587 285 2

488.679 286 2

499.746 287 2

505.682 288 2

486.704 289 2

474.693 290 2

531.498 291 2

554.702 292 2

487.691 293 2

488.676 294 2

514.686 295 2

501.718 296 2

539.139 297 2

504.694 298 2

529.729 299 2

500.731 300 2

565.6 301 2

487.691 302 2

488.676 303 2

557.16 304 2

523.672 305 2

475.68 306 2

480.721 307 2

480.721 308 2

466.694 309 2

528.091 310 2

528.091 311 2

507.673 312 2

460.668 313 2

489.664 314 2

573.773 315 2

506.016 316 2

528.091 317 2

472.677 318 2

460.665 319 2

537.546 320 2

525.534 321 2

492.732 322 2

474.693 323 2

503.709 324 2

503.709 325 2

506.759 326 2

522.685 327 2

508.109 328 2

534.721 329 2

590.104 330 2

487.691 331 2

487.691 332 2

517.742 333 2

499.702 334 2

485.719 335 2

499.746 336 2

487.05 337 2

482.675 338 2

494.748 339 2

492.732 340 2

506.759 341 2

487.691 342 2

486.704 343 2

514.758 344 2

506.093 345 2

518.721 346 2

518.721 347 2

495.708 348 2

507.125 349 2

486.704 350 2

485.719 351 2

522.759 352 2

513.699 353 2

492.658 354 2

489.707 355 2

521.771 356 2

593.613 357 2

481.687 358 2

494.082 359 2

487.691 360 2

520.787 361 2

520.787 362 2

527.128 363 2

463.691 364 2

539.139 365 2

506.759 366 2

486.704 367 2

478.001 368 2

578.721 369 2

472.679 370 2

560.731 371 2

508.732 372 2

492.732 373 2

496.696 374 2

473.664 375 2

514.761 376 2

461.656 377 2

460.668 378 2

471.692 379 2

490.053 380 2

627.723 381 2

478.705 382 2

494.748 383 2

536.539 384 2

520.787 385 2

507.673 386 2

460.688 387 2

472.679 388 2

476.026 389 2

532.798 390 2

506.759 391 2

509.113 392 2

562.604 393 2

492.732 394 2

479.69 395 2

461.653 396 2

526.75 397 2

500.712 398 2

492.683 399 2

504.694 400 2

518.721 401 2

513.101 402 2

460.665 402 2

528.091 404 2

504.694 405 2

472.679 406 2

493.717 407 2

493.732 408 2

497.93 409 2

525.112 410 2

485.719 411 2

505.682 412 2

506.137 413 2

550.588 414 2

534.77 415 2

501.718 416 2

485.719 417 2

489.682 418 2

492.732 419 2

520.743 420 2

517.718 421 2

501.718 422 2

472.677 423 2

542.17 424 2

536.561 425 2

488.695 426 2

506.137 427 2

490.667 428 2

844.778 429 2

513.73 430 2

492.732 431 2

506.759 432 2

542.17 433 2

478.656 434 2

493.095 435 2

478.705 436 2

506.137 437 2

401.863 438 2

498.136 439 2

482.071 440 2

491.692 441 2

493.717 442 2

495.708 443 2

585.214 444 2

544.186 445 2

549.162 446 2

639.186 447 2

493.717 448 2

578.642 449 2

501.675 450 2

499.746 451 2

493.095 452 2

537.546 453 2

491.745 454 2

474.668 455 2

564.177 456 2

585.162 457 2

517.718 458 2

507.744 459 2

491.745 460 2

495.708 461 2

505.682 462 2

510.1 463 2

485.719 464 2

473.708 465 2

510.1 466 2

494.082 467 2

503.691 468 2

495.681 469 2

487.691 470 2

498.136 471 2

507.744 472 2

640.67 473 2

593.613 474 2

614.651 475 2

560.108 476 2

477.718 477 2

459.637 478 2

655.685 479 2

594.598 480 2

676.722 481 2

536.561 482 2

604.68 483 2

578.598 484 2

510.1 485 2

506.137 486 2

507.125 487 2

626.687 488 2

473.664 489 2

528.091 490 2

477.718 491 2

522.136 492 2

506.137 493 2

521.546 494 2

490.667 495 2

485.697 496 2

492.008 497 2

535.551 498 2

481.083 499 2

508.109 500 2

506.093 501 2

477.718 502 2

536.163 503 2

525.112

Compounds in Table 3 having a basic group or acidic group are depictedand named either as the free base acid or as the salt thereof. Dependingon the reaction and purification conditions, the compounds of Table 1may be isolated in either the free base form, or as a salt (such as HClsalt), or in both free base and salt forms.

The utility of the compounds in accordance with the present invention asinhibitors of β-secretase enzyme activity may be demonstrated bymethodology known in the art. Enzyme inhibition is determined asfollows.

ECL Assay: A homogeneous end point electrochemiluminescence (ECL) assayis performed using a biotinylated BACE substrate. The Km of thesubstrate is approximated at 50 μM. A typical reaction containsapproximately 0.6 nM enzyme, 0.25 μM of the substrate, and buffer (50 mMPipes, pH 6.5, 0.1 mg/ml BSA, 0.2% CHAPS, 15 mM EDTA and 1 mMdeferoxamine) in a total reaction volume of 100 μl. The reactionproceeds for 1-2 hrs and is then stopped by the addition of 150 μL of aquench cocktail solution (25 μl M Tris-HCl, pH 8.0, 50 μl INC buffer (2%BSA, 0.2% Tween-20 and 0.05% sodium azide diluted in Phosphate bufferedsaline (PBS) plus 75 μL PBS), containing Streptavidin coated magneticbeads and ruthenylated antibody which specifically recognizes theC-terminal residue of the product. The samples are subjected to M-384(Igen Inc., Gaithersburg, Md.) analysis. Under these conditions, lessthan 10% of substrate is processed by BACE 1. The enzyme used in thesestudies is soluble (transmembrane domain and cytoplasmic extensionexcluded) human protein produced in a baculovirus expression system. Tomeasure the inhibitory potency for compounds, 10 concentrations ofinhibitors are prepared starting from 200 μM with three fold seriesdilution. Solutions of the inhibitor in DMSO are included in thereaction mixture (final DMSO concentration is 10%). All experiments areconducted at rt using the standard reaction conditions described above.To determine the IC₅₀ of the compound, a four parameter equation is usedfor curve fitting. The errors in reproducing the dissociation constantsare typically less than two-fold.

In particular, the compounds of the following examples had activity ininhibiting the beta-secretase enzyme in the aforementioned assay,generally with an IC₅₀ from about 1 nM to 200 μM. Such a result isindicative of the intrinsic activity of the compounds in use asinhibitors of beta-secretase enzyme activity.

Several methods for preparing the compounds of this invention areillustrated in the Schemes and Examples herein. Starting materials aremade according to procedures known in the art or as illustrated herein.The following examples are provided so that the invention might be morefully understood. These examples are illustrative only and should not beconstrued as limiting the invention in any way.

Exemplary IC₅₀ values for representative compounds of the invention (asdescribed in the following Examples) are provided below in Table 3.

TABLE 3 Example IC₅₀(μM) 3 2.19 7 22 10 20 19 0.92 21 0.071 30 14 310.024 38 12 44 19 77 0.2 100 0.45

The following abbreviations are used throughout the text:

Me: methylEt: ethylBu: butylt-Bu: tert-butyli-Bu: iso-butylPr: propyli-Pr: iso-propylAr: arylPh: phenylBn: benzylBOP: benzotriazolyl-N-oxy-tris(dimethylamino)phosphoniumhexafluorophosphateBoc: tert butyloxycarbonylTFA: trifluoro acetic acidTHF: tetrahydrofuranAc: acetylaq: aqueousrt: room temperatureh: hoursmin: minutes

1. A compound of formula (I)

wherein: V is selected from the group consisting of (1) C, or (2) N, andthe dotted line leading to V represents an optional double bond, and ispresent when V is C and is absent when V is N; Q is selected from thegroup consisting of (1) ═CR¹⁰—, (2) ═N—, (3) —(N→O)⁻, (4) —O—, or (5)═S—; Y is selected from the group consisting of (1) ═CR¹⁰—, (2) —CR¹⁰═,(3) ═CR¹⁰—CR¹¹═, (4) ═CR¹⁰—N═, or (5)═N—CR¹⁰═; Z is selected from thegroup consisting of (1) ═CR¹⁰—, (2) —N—, (3) —O—, or (4) ═S—; providedthat Q, Y and Z together form a fused aromatic 5- or 6-membered ring;X¹-X² is selected from the group consisting of (1) —CR¹⁰R¹¹—CR¹²CR¹³—,(2) —CR¹⁰R¹¹—O—, (3) —O—CR¹⁰R¹¹—, (4) —CR¹⁰R¹¹—NR¹²—, (5)—NR¹²—CR¹⁰R¹¹—, (6) —CR¹⁰R¹¹—S(═O)mR¹²—, (7) —S(═O)mR¹²—,CR¹⁰R¹¹—, (8)—CR¹⁰R¹¹—CR¹²CR¹³—O—; (9) —CR¹⁰R¹¹—NR¹⁴CR¹²R¹³—, (10)—CR¹⁰R¹¹—O—CR¹²CR¹³—, (11) —CR¹⁰R¹¹—CR¹²CR¹³NR¹⁴—, or (12)—O—CR¹⁰R¹¹—CR¹²CR¹³—; R¹ is selected from the group consisting of (1)hydrogen, (2) C₁₋₆alkyl, (3) C₂₋₆alkenyl, (4) —C₃₋₉ cycloalkyl, (5)—C₆₋₁₀aryl, (6) heteroaryl group having from 5 to 12 ring atoms, whereinat least one ring atom is a heteroatom selected from the groupconsisting of nitrogen, sulfur or oxygen, (7) a heterocyclic grouphaving 4 to 8 ring atoms, wherein at least one ring atom is a heteroatomselected from the group consisting of nitrogen, sulfur or oxygen, andwherein said alkyl, alkenyl, aryl, cycloalkyl, heterocyclic orheteroaryl R² moiety is optionally substituted with one or more (a)halo, (b) —OH, (c) —CN, (d) —C₁₋₆ alkyl (e) —C₃₋₉ cycloalkyl, (f)—O—C₁₋₆ alkyl, (g) —O—CH₂—C₆₋₁₀aryl, (h) —C₆₋₁₀aryl, (i) heteroarylgroup having from 5 to 12 ring atoms, wherein at least one ring atom isa heteroatom selected from the group consisting of nitrogen, sulfur oroxygen, (j) oxo, (k) a heterocyclic group having 4 to 8 ring atoms,wherein at least one ring atom is a heteroatom selected from the groupconsisting of nitrogen, sulfur or oxygen, and (l) —O—CH₂—C₃₋₈cycloalkyl, (m) —C(═O)—C₁₋₆ alkyl, or (n) —NR^(5A)R^(5B); R² and R³ areindependently selected from the group consisting of (1) hydrogen, (2)OH, (3) —C₁₋₆ alkyl (4) —CN, (5) —C₆₋₁₀ aryl, or (6) heteroaryl grouphaving from 5 to 12 ring atoms, wherein at least one ring atom is aheteroatom selected from the group consisting of nitrogen, sulfur oroxygen, wherein said alkyl, aryl or heteroaryl R² and R³ moiety isoptionally substituted with one or more (a) halo, (b) —C₁₋₆ alkyl,wherein said alkyl is optionally substituted with one or more halogen,and (c) —O—C₁₋₆ alkyl, or R² and R³ are linked together to form cyclicgroup of 4-10 ring carbon atoms, wherein one or two of the ring carbonatoms is replaced by an oxygen, nitrogen or sulfur; R^(5A) and R^(5B)are independently selected from the group consisting of (1) hydrogen,(2) —C₁₋₆ alkyl, (3) —C(═O)—(O)_(m)—C₁₋₆ alkyl, (4) —C(═O)—(O)_(m)—C₆₋₁₀aryl, (5) —SO₂—C₃₋₈ cycloalkyl, (6) —SO₂—C₁₋₆ alkyl, (4)—C(═O)—NR^(6A)R^(6B), wherein R^(6A) and R^(6B) are selected from thegroup consisting of wherein the alkyl, cycloalkyl or aryl moiety isoptionally substituted with one or more (a) halogen, (b) hydroxyl, (c)—O—C₁₋₆ alkyl, or (d) —C(═O)—(O)_(m)—C₁₋₆ alkyl, or R^(6A) and R^(6B)are linked together with the nitrogen to which they are attached to forma 4-6 membered carbocyclic ring, wherein one or two of the ring carbonatoms is optionally replaced by a nitrogen, oxygen or sulfur, and thering is optionally substituted with one or more (a) halogen, (b)hydroxyl, (c) C₁₋₆ alkyl, (d) —O—C₁₋₆ alkyl, (e) —C(═O)—(O)_(m)—C₁₋₆alkyl, or (f) —SO₂—C₁₋₆ alkyl; R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ areindependently selected from the group consisting of: (1) hydrogen, (2)—C₁₋₆ alkyl, (3) hydroxyl, (4) —(CH₂)_(m)C₆₋₁₀aryl, (5) —C₂₋₆alkenyl,(6) —O—C₁₋₆alkyl, (7) halogen, (8) —SO₂—C₁₋₆alkyl, (9) —NR^(5A)R^(5B),(10) —C₃₋₈ cycloalkyl, (11) —C(═O)—(O)_(m)—C₁₋₆ alkyl, (12)—C(═O)—(O)_(m)—C₆₋₁₀aryl, (13) —C(═O)—NH—C₁₋₆alkyl, (14) —S(═O)₂—C₆₋₁₀aryl, wherein said alkyl, cycloalkyl, alkenyl or aryl moiety isoptionally substituted with one or more (a) halo, (b) hydroxyl, (c)—C₁₋₆ alkyl, (d) —NR^(5A)R^(5B), (e) —O—C₁₋₆ alkyl, and (f) —C₆₋₁₀aryl,wherein said wherein said alky or aryl is optionally substituted withone or more halo, or any R¹⁰ and R¹¹, or any R¹² and R¹³, on identicalcarbon ring atoms, are linked together to form an oxo group, or any R¹⁰and R¹¹, or any R¹² and R¹³, on identical carbon ring atoms, are linkedtogether to form an aromatic or non-aromatic spirocyclic group of 5-10ring carbon atoms, wherein one or two of the ring carbon atoms isreplaced by an oxygen, nitrogen or sulfur, or any R¹⁰ and R¹¹, or anyR¹² and R¹³, on adjacent carbon ring atoms, are linked together to formto form a fused aromatic or non-aromatic cyclic group of 5-10 ringcarbon atoms, wherein one or two of the ring carbon atoms is replaced byan oxygen, nitrogen or sulfur, m is 0 or 1; n is 0 or 1; p is 0, 1 or 2;or a pharmaceutically acceptable salt thereof.
 2. A compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein -Q-Y—Z— togetherform the group —CR¹⁰═CR¹⁰—CR¹¹═CR¹⁰—, thereby forming a fused phenylring.
 3. A compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein -Q-Y—Z— together forms the groups CR¹⁰—CR¹¹═CR¹⁰— or—CR¹⁰═CR¹⁰—CR¹¹═N—, thereby forming a fused pyridyl ring.
 4. A compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein-Q-Y—Z— together forms the groups —N═CR¹⁰—CR¹¹═N— or —N═CR¹⁰—N═CR¹¹—,thereby forming a fused pyrimidinyl ring.
 5. A compound of claim 1, or apharmaceutically acceptable salt thereof, wherein -Q-Y—Z— together formsthe groups —NH—CR¹⁰═CR¹⁰—, —S—CR¹⁰═CR¹⁰—, —O—CR¹⁰═CR¹⁰—, —N═CR¹⁰—S—,—CR¹⁰═CR¹⁰═S— or —CR¹⁰═CR¹⁰—O—, thereby forming a five-memberedheteroaryl ring.
 6. A compound of any of claims 1 to 5, or apharmaceutically acceptable salt thereof, wherein X¹-X² is—CR¹⁰R¹¹—CR¹²CR¹³— and n is 0 or
 1. 7. A compound of any of claims 1 to5, or a pharmaceutically acceptable salt thereof, wherein X¹-X² isNR¹²—CR¹⁰R¹¹— or —CR¹⁰R¹¹—NR¹²— and n is
 1. 8. A compound of any ofclaims 1 to 5, or a pharmaceutically acceptable salt thereof, whereinX¹-X² is —S(═)pR¹²—CR¹⁰R¹¹— and n is
 1. 9. A compound of any of claims 1to 5, or a pharmaceutically acceptable salt thereof, wherein X¹-X² is—CR¹⁰R¹¹—O— or —O—CR¹⁰R¹¹—, and n is
 1. 10. A compound of any of claims1 to 9, wherein R¹ is selected from the group consisting of (1) hydrogen(2) C₁₋₆alkyl, (3) C₃₋₉ cycloalkyl, or (4) phenyl, wherein said alkyl,cycloalkyl or phenyl R¹ moiety is optionally substituted with one ormore (a) halo, (b) —OH, (c) —CN, (d) —C₁₋₆ alkyl (e) —C₃₋₆ cycloalkyl,or (f) —O—C₁₋₆ alkyl.
 11. A compound of any of claims 1 to 10, whereinR² is hydrogen and R³ is selected from the group consisting of: (1)hydrogen, (2) aryl, or (3) heteroaryl, wherein said aryl or heteroarylR³ moiety is optionally substituted with one or more (a) halo, (b) —C₁₋₆alkyl, wherein said alkyl is optionally substituted with one or morehalogen, and (c) —O—C₁₋₆ alkyl.
 12. A compound of claim 1, wherein thecompound of formula (I) is a compound of formula (II)

or a pharmaceutically acceptable salt thereof, wherein R², R⁵, X¹, X²,Q, Y and Z are as defined above.
 13. A compound of claim 1, wherein thecompound of formula (I) is a compound of formula (III)

or a pharmaceutically acceptable salt thereof, wherein R², R⁵, X¹, X²,Q, Y and Z are as defined above.
 14. A compound of claim 1, wherein thecompound of formula (I) is a compound of formula (IV)

or a pharmaceutically acceptable salt thereof, wherein R², R³, R⁴, R⁵,X¹ and X² are as defined above.
 15. A compound of claim 1, wherein thecompound of formula (I) is a compound of formula (V)

or a pharmaceutically acceptable salt thereof, wherein R², R³, R⁴, R⁵,X¹ and X² are as defined above.
 16. A compound of claim 1, which isselected from the group consisting of:4′-[(4-phenylpiperidin-1-yl)carbonyl]-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidine];[(1R,4′S)-6-methyl-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl](4-phenylpiperidin-1-yl)methanone;[(4R,4′S)-8-methoxy-2,3-dihydrospiro[chromene-4,3′-pyrrolidin]-4′-yl][(2S,4R)-2-(3,3-difluorocyclohexyl)-4-phenylpiperidin-1-yl]methanone;(1R,4′S)-2,3-dihydrospiro[indene-1,3′-pyrrolidin]-4′-yl(4-phenylpiperidin-1-yl)methanone;(1R,4′S)-2,3-dihydrospiro[indene-1,3′-pyrrolidin]-4′-yl[(2S,4R)-4-phenyl-2-(propan-2-yl)piperidin-1-yl]methanone;(1R,4′S)-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl(4-phenylpiperidin-1-yl)methanone;(4R,4′S)-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl[(2S,4R)-4-phenyl-2-(propan-2-yl)piperidin-1-yl]methanone;(4R,4′S)-2,3-dihydrospiro[chromene-4,3′-pyrrolidin]-4′-yl(4-phenylpiperidin-1-yl)methanone;(1R,4′S)-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl[(2S,4R)-2,4-diphenylpiperidin-1-yl]methanone;(1S,4′S)-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl[2-(2-methoxypropan-2-yl)piperidin-1-yl]methanone;[(1R,4′S)-4,4-dimethyl-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl](4-phenylpiperidin-1-yl)methanone;[(2S,4R)-2-cyclohexyl-4-phenylpiperidin-1-yl][(1R,4′S)-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl]methanone;[(2R,4S)-2-cyclohexyl-4-phenylpiperidin-1-yl][(1R,4′S)-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl]methanone;[(1R,4′S)-7-bromo-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl](4-phenylpiperidin-1-yl)methanone;(1S,4′S)-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl[2-(3-methoxypentan-3-yl)piperidin-1-yl]methanone;[(2S,4R)-2-cyclohexyl-4-phenylpiperidin-1-yl][(1R,4′S)-2,3-dihydrospiro[indene-1,3′-pyrrolidin]-4′-yl]methanone;[(1R,4′S)-6-bromo-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl](4-phenylpiperidin-1-yl)methanone,[(1R,4′S)-6-methoxy-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl](4-phenylpiperidin-1-yl)methanone;[(1R,4′S)-6-chloro-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl](4-phenylpiperidin-1-yl)methanone;[(1R,4′S)-6-bromo-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl](1′H-spiro[indene-1,4′-piperidin]-1′-yl)methanone;(1R,4′S)-2,3-dihydrospiro[indene-1,3′-pyrrolidin]-4′-yl[(2S,4R)-2,4-diphenylpiperidin-1-yl]methanone;[(1R,4′S)-6-bromo-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl][(2S,4R)-2,4-diphenylpiperidin-1-yl]methanone;(1S,4′S)-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl(4-phenylpiperidin-1-yl)methanone;(3R,4S)-2′,3′-dihydro-1′H-spiro[pyrrolidine-3,4′-quinolin]-4-yl(4-phenylpiperidin-1-yl)methanone;[(1R,4′S)-6-bromo-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl][(2S,4R)-4-phenyl-2-(propan-2-yl)piperidin-1-yl]methanone;[(1R,4′S)-6-hydroxy-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl](4-phenylpiperidin-1-yl)methanone;[(1R,4′S)-6-bromo-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl](4-phenylpiperidin-1-yl)methanone;[(1R,4′S)-6-fluoro-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl](4-phenylpiperidin-1-yl)methanone;(3R,4S)-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl(4-phenylpiperidin-1-yl)methanone;[(1R,4′S)-5-bromo-2,3-dihydrospiro[indene-1,3′-pyrrolidin]-4′-yl](4-phenylpiperidin-1-yl)methanone;(4-phenylpiperidin-1-yl)[(1R,4′S)-5-(propan-2-yl)-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl]methanone;[(1R,4′S)-6-bromo-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl][(2S,4R)-2-cyclohexyl-4-phenylpiperidin-1-yl]methanone;[(1R,4′S)-6-bromo-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl][(2R,4S)-2-cyclohexyl-4-phenylpiperidin-1-yl]methanone;[(3R,4S)-1′-(methylsulfonyl)-2′,3′-dihydro-1′H-spiro[pyrrolidine-3,4′-quinolin]-4-yl](4-phenylpiperidin-1-yl)methanone;[(3R,4S)-2′-chloro-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl](4-phenylpiperidin-1-yl)methanone;[(3R,4S)-2′-chloro-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl][(2S,4R)-4-phenyl-2-(propan-2-yl)piperidin-1-yl]methanone;[(3R,4S)-2′-bromo-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl](4-phenylpiperidin-1-yl)methanone;(3R,4S)-2′,3′-dihydrospiro[pyrrolidine-3,4′-thiochromen]-4-yl(4-phenylpiperidin-1-yl)methanone;[(3R,4S)-2′-(dimethylamino)-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl](4-phenylpiperidin-1-yl)methanone;[(3R,4S)-2′-(methylamino)-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl](4-phenylpiperidin-1-yl)methanone;[(1R,4′S)-6-ethenyl-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl](4-phenylpiperidin-1-yl)methanone;[(1R,4′S)-5-amino-2,3-dihydrospiro[indene-1,3′-pyrrolidin]-4′-yl](4-phenylpiperidin-1-yl)methanone;[(1R,4′S)-5-(dimethylamino)-2,3-dihydrospiro[indene-1,3′-pyrrolidin]-4′-yl](4-phenylpiperidin-1-yl)methanone;[(1R,4′S)-6-ethyl-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl](4-phenylpiperidin-1-yl)methanone;(4S,4′S)-2,3-dihydro-1H-spiro[isoquinoline-4,3′-pyrrolidin]-4′-yl(4-phenylpiperidin-1-yl)methanone;[(3R,4S)-2′-chloro-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl](4-phenylpiperidin-1-yl)methanone;[(3R,4S)-1′,1′-dioxido-2′,3′-dihydrospiro[pyrrolidine-3,4′-thiochromen]-4-yl](4-phenylpiperidin-1-yl)methanone;[(1R,4′S)-6-methyl-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl](4-phenylpiperidin-1-yl)methanone;(4-phenylpiperidin-1-yl)[(1R,4′S)-6-(propan-2-yl)-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl]methanone;[(3R,4S)-2′-methyl-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl](4-phenylpiperidin-1-yl)methanone;[(3R,4S)-2′-chloro-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl][(2R,4S)-2-cyclohexyl-4-phenylpiperidin-1-yl]methanone;[(3R,4S)-2′-chloro-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl][(2S,4R)-2-cyclohexyl-4-phenylpiperidin-1-yl]methanone;[(3R,4S)-2′-chloro-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl][(2R,4R)-2-cyclohexyl-4-phenylpiperidin-1-yl]methanone;[(3R,4S)-2′-chloro-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl][(2S,4S)-2-cyclohexyl-4-phenylpiperidin-1-yl]methanone;[(1R,4′S)-6-(morpholin-4-yl)-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl](4-phenylpiperidin-1-yl)methanone;[(1R,4′S)-6-tert-butyl-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl](4-phenylpiperidin-1-yl)methanone;[(2S,4R)-2-cyclohexyl-4-phenylpiperidin-1-yl][(3R,4S)-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl]methanone;[(1R,4′S)-6-cyclopropyl-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl](4-phenylpiperidin-1-yl)methanone;(4-phenylpiperidin-1-yl)[(1R,4′S)-6-(trifluoromethyl)-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl]methanone;[(3R,4S)-2′-chloro-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl][(2S,4R)-2,4-diphenylpiperidin-1-yl]methanone;[(2S,4R)-2,4-diphenylpiperidin-1-yl][(3R,4S)-2′-methyl-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl]methanone;[(3R,4S)-2′-bromo-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl][(2S,4R)-2-cyclohexyl-4-phenylpiperidin-1-yl]methanone;[(2S,4R)-2-cyclohexyl-4-phenylpiperidin-1-yl][(3R,4S)-2′-methyl-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl]methanone;[(1R,4′S)-6-(difluoromethyl)-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl](4-phenylpiperidin-1-yl)methanone;[(1R,4′S)-6-(hydroxymethyl)-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl](4-phenylpiperidin-1-yl)methanone;[(1R,4′S)-6-(aminomethyl)-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl](4-phenylpiperidin-1-yl)methanone;[(1R,4′S)-6-(fluoromethyl)-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl](4-phenylpiperidin-1-yl)methanone;[(2S,4R)-2-cyclohexyl-4-phenylpiperidin-1-yl][(4S,4′S)-2,3-dihydro-1H-spiro[isoquinoline-4,3′-pyrrolidin]-4′-yl]methanone;[(2S,4R)-2-cyclohexyl-4-phenylpiperidin-1-yl][(4R,4′R)-2,3-dihydro-1H-spiro[isoquinoline-4,3′-pyrrolidin]-4′-yl]methanone;[(2S,4R)-2-cyclohexyl-4-phenylpiperidin-1-yl][(3R,4S)-2′-(propan-2-yl)-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl]methanone;(4-phenylpiperidin-1-yl)[(1R,4′S)-6-(2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl]methanone;[(3R,4S)-2′-methyl-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl][(2S,4R)-4-phenyl-2-(propan-2-yl)piperidin-1-yl]methanone;[(2S,4R)-2-cyclohexyl-4-phenylpiperidin-1-yl][(3R,4S)-1′-oxido-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl]methanone;[(2S,4R)-2-tert-butyl-4-phenylpiperidin-1-yl][(3R,4S)-2′-methyl-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl]methanone;(4-phenylpiperidin-1-yl)[(4S,4′S)-1H-spiro[isochromene-4,3′-pyrrolidin]-4′-yl]methanone;[(3R,4S)-2′-chloro-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl][(2S,4R)-2-(pentan-3-yl)-4-phenylpiperidin-1-yl]methanone;[(3R,4S)-2′-chloro-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl](2′-phenyl-1′H-spiro[indene-1,4′-piperidin]-1′-yl)methanone;[(3R,4S)-2′-chloro-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl](2′-phenyl-1′H-spiro[indene-1,4′-piperidin]-1′-yl)methanone;[(3R,4S)-2′-chloro-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl](2′-phenyl-1′H-spiro[indene-1,4′-piperidin]-1′-yl)methanone;[(3R,4S)-2′-methyl-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl][(2S,4R)-2-(pentan-3-yl)-4-phenylpiperidin-1-yl]methanone;[(2S,4R)-2-cyclohexyl-4-phenylpiperidin-1-yl][(1R,4′S)-6-(hydroxymethyl)-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidin]-4′-yl]methanone;[(4S)-2′-chloro-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl](4-phenyl-2-propylpiperidin-1-yl)methanone;[(4S)-2′-chloro-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl][2-(2-methylpropyl)-4-phenylpiperidin-1-yl]methanone;[(4S)-2′-chloro-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl](4-phenyl-2-propylpiperidin-1-yl)methanone;[(4S)-2′-chloro-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl][2-(4-fluorophenyl)-4-phenylpiperidin-1-yl]methanone;2,3-dihydrospiro[chromene-4,3′-pyrrolidin]-4′-yl(2,4-diphenylpiperidin-1-yl)methanone;(6-bromo-2,3-dihydrospiro[indene-1,3′-pyrrolidin]-4′-yl)[2-(4-fluorophenyl)-4-phenylpiperidin-1-yl]methanone;[(3R,4S)-2′-chloro-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl](4-phenyl-2-propylazepan-1-yl)methanone;(6-bromo-2,3-dihydrospiro[indene-1,3′-pyrrolidin]-4′-yl)(2,4-diphenylpiperidin-1-yl)methanone;(2′-chloro-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl)(2,4-diphenylpiperidin-1-yl)methanone;(2′-chloro-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl)(2,4-diphenylpiperidin-1-yl)methanone;2,3-dihydrospiro[chromene-4,3′-pyrrolidin]-4′-yl[4-phenyl-2-(prop-2-en-1-yl)piperidin-1-yl]methanone;2,3-dihydrospiro[chromene-4,3′-pyrrolidin]-4′-yl[2-(2-fluorophenyl)-4-phenylpiperidin-1-yl]methanone;2,3-dihydrospiro[chromene-4,3′-pyrrolidin]-4′-yl[2-(4-fluorophenyl)-4-phenylpiperidin-1-yl]methanone;(2,4-diphenylpiperidin-1-yl)(6-ethyl-2,3-dihydrospiro[indene-1,3′-pyrrolidin]-4′-yl)methanone;(3-benzylpiperidin-1-yl)[(3R,4S)-2′-chloro-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl]methanone;[(3R,4S)-2′-chloro-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl](1′H-spiro[1-benzofuran-3,4′-piperidin]-1′-yl)methanone;[(3R,4S)-2′-chloro-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl](1,2-dihydro-1′H-spiro[indole-3,4′-piperidin]-1′-yl)methanone;(2-butyl-2,3-dihydrospiro[chromene-4,3′-pyrrolidin]-4′-yl)(2,4-diphenylpiperidin-1-yl)methanone;(2′-chloro-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl)(5-phenyl-2-propylazepan-1-yl)methanone;(2′-chloro-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl)[4-phenyl-2-(prop-2-en-1-yl)piperidin-1-yl]methanone;(2′-chloro-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl)[2-(2-fluorophenyl)-4-phenylpiperidin-1-yl]methanone;[(3R,4S)-2′-chloro-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl][2-(3-methylphenyl)-4-phenylpiperidin-1-yl]methanone;(4R,4′S)-2,3-dihydrospiro[chromene-4,3′-pyrrolidin]-4′-yl[(2S,4R)-2,4-diphenylpiperidin-1-yl]methanone;[(2S,4R)-2,4-diphenylpiperidin-1-yl][(4R,4′S)-2-methyl-2,3-dihydrospiro[chromene-4,3′-pyrrolidin]-4′-yl]methanone;[(4R,4′S)-2-butyl-2,3-dihydrospiro[chromene-4,3′-pyrrolidin]-4′-yl][(2S,4R)-2,4-diphenylpiperidin-1-yl]methanone;[(4R,4′S)-6-chloro-2,3-dihydrospiro[chromene-4,3′-pyrrolidin]-4′-yl][(2S,4R)-2,4-diphenylpiperidin-1-yl]methanone;[(4R,4′S)-6-chloro-7-methyl-2,3-dihydrospiro[chromene-4,3′-pyrrolidin]-4′-yl][(2S,4R)-2,4-diphenylpiperidin-1-yl]methanone;[(3R,4S)-2′-chloro-1′-oxido-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl][(2R,4S)-2,4-diphenylpiperidin-1-yl]methanone;[(2R,4S)-2,4-diphenylpiperidin-1-yl][(3R,4S)-2′-ethyl-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl]methanone;[(3R,4S)-2′-chloro-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl][2′-(4-fluorophenyl)-1′H-spiro[indene-1,4′-piperidin]-1′-yl]methanone;[(3R,4S)-2′-chloro-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinolin]-4-yl](2′-phenyl-1′H-spiro[indene-1,4′-piperidin]-1′-yl)methanone;(4R,4′S)-4′-{[(2S,4R)-2,4-diphenylpiperidin-1-yl]carbonyl}-1,5,6,7-tetrahydrospiro[indole-4,3′-pyrrolidine];(4R,4′S)-4′-{[(2S,4R)-2,4-diphenylpiperidin-1-yl]carbonyl}-6,7-dihydro-5H-spiro[1-benzothiophene-4,3′-pyrrolidine];(4R,4′S)-4′-{[(2S,4R)-2,4-diphenylpiperidin-1-yl]carbonyl}-6,7-dihydro-5H-spiro[1-benzofuran-4,3′-pyrrolidine];(4R,4′S,7S)-4′-{[(2S,4R)-2,4-diphenylpiperidin-1-yl]carbonyl}-2-methyl-5,6-dihydro-4H-spiro[1,3-benzothiazole-7,3′-pyrrolidine];(4′S,7S)-4′-{[(2S,4R)-2,4-diphenylpiperidin-1-yl]carbonyl}-5,6-dihydro-4H-spiro[1-benzothiophene-7,3′-pyrrolidine];(4′S,7S)-4′-{[(2S,4R)-2,4-diphenylpiperidin-1-yl]carbonyl}-5,6-dihydro-4H-spiro[1-benzofuran-7,3′-pyrrolidine];(3R,4S)-4-{[(2S,4R)-2,4-diphenylpiperidin-1-yl]carbonyl}-7′-methyl-2′,3′-dihydrospiro[pyrrolidine-3,4′-thiopyrano[2,3-b]pyridine];(3S,4S)-2′-chloro-4-{[(2S,4R)-2,4-diphenylpiperidin-1-yl]carbonyl}-6′,7′-dihydro-5′H-spiro[pyrrolidine-3,8′-quinoline];(3R,4S)-3′-chloro-4-{[(2S,4R)-2,4-diphenylpiperidin-1-yl]carbonyl}-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinoline];(3S,4S)-4-{[(2S,4R)-2,4-diphenylpiperidin-1-yl]carbonyl}-2′-phenyl-6′,7′-dihydro-5′H-spiro[pyrrolidine-3,8′-quinoline];(3R,4S)-4-{[(2S,4R)-2,4-diphenylpiperidin-1-yl]carbonyl}-3′-methyl-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinoline];(3R,4S)-4-{[(2S,4R)-2,4-diphenylpiperidin-1-yl]carbonyl}-4′-methyl-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinoline];(3S,4S)-4-{[(2S,4R)-2,4-diphenylpiperidin-1-yl]carbonyl}-3′-methyl-6′,7′-dihydro-5′H-spiro[pyrrolidine-3,8′-quinoline];(3R,4S)-4-{[(2S,4R)-2,4-diphenylpiperidin-1-yl]carbonyl}-2′-methyl-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinazoline];(3R,4S)-4-{[(2S,4R)-2,4-diphenylpiperidin-1-yl]carbonyl}-2′-phenyl-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinazoline];(3S,4S)-4-{[(2S,4R)-2,4-diphenylpiperidin-1-yl]carbonyl}-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinoxaline];(3R,4S)-4-{[(2S,4R)-2,4-diphenylpiperidin-1-yl]carbonyl}-4′-(trifluoromethyl)-7′,8′-dihydro-6′H-spiro[pyrrolidine-3,5′-quinoline];(4′S,8R)-4′-{[(2S,4R)-2,4-diphenylpiperidin-1-yl]carbonyl}-1,3-dimethyl-6,7-dihydro-5H-spiro[isoquinoline-8,3′-pyrrolidine];(1R,4′S)-4′-{[(2S,4R)-2,4-diphenylpiperidin-1-yl]carbonyl}-6,8-dimethyl-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidine];(1R,4′S)-4′-{[(2S,4R)-2,4-diphenylpiperidin-1-yl]carbonyl}-3,4,5,6,7,8-hexahydro-2H-spiro[acridine-1,3′-pyrrolidine];(4′S,9R)-4′-{[(2S,4R)-2,4-diphenylpiperidin-1-yl]carbonyl}-1,2,3,6,7,8-hexahydrospiro[cyclopenta[c]quinoline-9,3′-pyrrolidine];(4R,4′S)-4′-{[(2S,4R)-2,4-diphenylpiperidin-1-yl]carbonyl}-2,2-dimethyl-2,3-dihydrospiro[chromene-4,3′-pyrrolidine];(4R,4′S)-7-bromo-4′-{[(2S,4R)-2,4-diphenylpiperidin-1-yl]carbonyl}-2,3-dihydrospiro[chromene-4,3′-pyrrolidine];(3S,4′S)-6-bromo-4′-{[(2S,4R)-2,4-diphenylpiperidin-1-yl]carbonyl}spiro[1-benzofuran-3,3′-pyrrolidine];(1R,4′S)-5-bromo-4′-{[(2S,4R)-2,4-diphenylpiperidin-1-yl]carbonyl}-2,3-dihydrospiro[indene-1,3′-pyrrolidine];(1S,4′S)-7-bromo-4′-{[(2S,4R)-2,4-diphenylpiperidin-1-yl]carbonyl}-4,5-dihydrospiro[3-benzoxepine-1,3′-pyrrolidine];or a pharmaceutically acceptable salt thereof.
 17. A compound of claim1, which is selected from the group consisting of Structure

or a pharmaceutically acceptable salt thereof.
 18. A pharmaceuticalcomposition, comprising a therapeutically effective amount of a compoundof any of claims 1-17, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier.
 19. (canceled)
 20. A methodof treating a disease or disorder selected from the group consisting ofAlzheimer's Disease, mild cognitive impairment, Trisomy 21 (Down'sSyndrome), cerebral amyloid angiopathy, degenerative dementia,Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type(HCHWA-D), Creutzfeld-Jakob disease, prion disorder, amyotrophic lateralsclerosis, progressive supranuclear palsy, head trauma, stroke,pancreatitis, inclusion body myositis, diabetes and atherosclerosis,said method comprising administering a pharmacologically effectiveamount to a patient in need thereof a compound of any of claims 1-17, ora pharmaceutically acceptable salt thereof.
 21. A method of claim 20,wherein said disease or disorder is Alzheimer's Disease